id stringlengths 24 24 | contexts_ids listlengths 1 157 | split stringclasses 1 value | question stringlengths 13 215 | type stringclasses 4 values | answer stringlengths 2 3.15k | exact_answer stringlengths 1 3.15k | contexts listlengths 1 157 | concepts stringlengths 3 7.42k |
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61f52fca882a024a10000003 | [
34249907,
34423300
] | train | Which syndromes are caused by LAMA1 mutations? | list | Poretti-Boltshauser and Joubert syndromes | ['Poretti-Boltshauser syndrome', 'Joubert syndrome'] | [
"BACKGROUND: High myopia with alopecia areata in the occipital region has been \nobserved in patients with Knobloch syndrome caused by COL18A1 mutations. This \nstudy investigated other possible genetic causes of high myopia in patients with \nalopecia areata in the cranial midline.\nMETHODS: Six patients with early onset high myopia and alopecia areata in the \ncranial midline were recruited. Targeted high-throughput sequencing was \nperformed on the proband's DNA to detect potential pathogenic variants. \nCosegregation analysis was performed for available family members. Minigene \nassay and RNA Sequencing were used to validate the abnormality of possible \nsplicing change and gross deletion. Ophthalmological and neuroimaging \nexaminations were performed.\nRESULTS: Eight novel and one known loss-of-function mutants were detected in all \nsix patients, including a gross deletion detected by RNA sequencing. Four \nCOL18A1 mutants in three patients with scalp leisure in the occipital region; \nand five LAMA1 mutations in three patients with scalp leisure in the parietal \nregion. Further assessments indicated that patients with COL18A1 mutations had \nKnobloch syndrome, and the patients with LAMA1 mutations had Poretti-Boltshauser \nsyndrome.\nCONCLUSION: Our study found that early onset high myopia with midline alopecia \nareata could be caused not only by mutations of the COL18A1 gene but also by \nmutations in the LAMA1 gene. To our knowledge, we are the first to observe scalp \ndefects in patients with LAMA1 mutations. High myopia with alopecia areata in \nthe cranial midline could be treated as an early diagnostic clue for \nophthalmologists to consider the two kinds of rare diseases.",
"Paediatric neurology syndromes are a broad and complex group of conditions with \na large spectrum of clinical phenotypes. Joubert syndrome is a genetically \nheterogeneous neurological ciliopathy syndrome with molar tooth sign as the \nneuroimaging hallmark. We reviewed the clinical, radiological and genetic data \nfor several families with a clinical diagnosis of Joubert syndrome but negative \ngenetic analysis. We detected biallelic pathogenic variants in LAMA1, including \nnovel alleles, in each of the four cases we report, thereby establishing a firm \ndiagnosis of Poretti-Boltshauser syndrome. Analysis of brain MRI revealed \ncerebellar dysplasia and cerebellar cysts, associated with Poretti-Boltshauser \nsyndrome and the absence of typical molar tooth signs. Using large UK patient \ncohorts, the relative prevalence of Joubert syndrome as a cause of intellectual \ndisability was 0.2% and of Poretti-Boltshauser syndrome was 0.02%. We conclude \nthat children with congenital brain disorders that mimic Joubert syndrome may \nhave a delayed diagnosis due to poor recognition of key features on brain \nimaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We \nadvocate the inclusion of LAMA1 genetic analysis on all intellectual disability \nand Joubert syndrome gene panels and promote a wider awareness of the clinical \nand radiological features of these syndromes."
] | nan |
5881f627713cbdfd3d000005 | [
27199372
] | train | Which technique led to the elucidation of the role of HOXD10 in regulating lymphatic endothelial responses to VEGF-C? | factoid | DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C. | DeepCAGE | [
"Author information:\n(1)Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical \nSciences, ETH Zurich, Zurich 8093, Switzerland.\n(2)Centre for Molecular Medicine and Therapeutics, Child and Family Research \nInstitute, Department of Medical Genetics, University British Columbia, \nVancouver, British Columbia, Canada V5Z 4H4.\n(3)Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris \nComprehensive Cancer Center, University of Southern California, Los Angeles, CA \n90033, USA.\n(4)RIKEN Center for Life Science Technologies, Division of Genomic Technologies, \nYokohama, Kanagawa 230-0045, Japan.\n(5)RIKEN Center for Life Science Technologies, Division of Genomic Technologies, \nYokohama, Kanagawa 230-0045, Japan Telethon Kids Institute, The University of \nWestern Australia, Subiaco, Western Australia 6008, Australia.\n(6)RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama \n351-0198, Japan.\n(7)RIKEN Center for Life Science Technologies, Division of Genomic Technologies, \nYokohama, Kanagawa 230-0045, Japan Cancer and Cell Biology Division, Harry \nPerkins Institute of Medical Research, QEII Medical Centre and Centre for \nMedical Research, the University of Western Australia, Nedlands, Western \nAustralia 6009, Australia.\n(8)Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical \nSciences, ETH Zurich, Zurich 8093, Switzerland michael.detmar@pharma.ethz.ch."
] | ['http://www.uniprot.org/uniprot/VEGFC_MOUSE', 'http://www.uniprot.org/uniprot/HXD10_SAGLB', 'http://www.uniprot.org/uniprot/HXD10_HUMAN', 'http://www.uniprot.org/uniprot/HXD10_HETFR', 'http://www.uniprot.org/uniprot/HXD10_LAGLA', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004729', 'http://www.uniprot.org/uniprot/VEGFC_HUMAN', 'http://www.uniprot.org/uniprot/VEGFC_RAT', 'http://www.biosemantics.org/jochem#4263666', 'http://www.uniprot.org/uniprot/HXD10_CHICK', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D042582', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D040262', 'http://www.uniprot.org/uniprot/HXD10_PANTR', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D042442', 'http://amigo.geneontology.org/amigo/term/GO:0036328'] |
5a68ff52b750ff445500001c | [
3488531,
28765477,
26007263
] | train | Which tendons are affected in the Dequervain's tenosynovitis? | list | DeQuervain's tenosynovitis is a common cause of radial-sided wrist pain. Symptoms result from a narrow first dorsal compartment and associated tendinosis of the enclosed extensor pollicis brevis and/or abductor pollicis longus. | ['extensor pollicis brevis', 'abductor pollicis longus'] | [
"DeQuervain tenosynovitis, which involves the abductor pollicis longus and \nextensor pollicis brevis tendons, is much more common in women than men and is \ndue to repetitive movements of the hand such as grasping and twisting. \nHousewives and persons involved in manual occupations using the hands and wrists \naccount for most cases in previous series. In this series, six of 24 female \npatients (25%) were pregnant or postpartum at the time of onset. In five of the \nsix, activities of infant care aggravated symptoms. Both pregnancy, per se, and \nmechanical factors appear to play a role in causing this condition.",
"DeQuervain's tenosynovitis is a common cause of radial-sided wrist pain. \nSymptoms result from a narrow first dorsal compartment and associated tendinosis \nof the enclosed extensor pollicis brevis and/or abductor pollicis longus (APL). \nSurgical intervention, offered when conservative measures fail to adequately \nrelieve symptoms, requires a detailed understanding of potentially aberrant \nanatomy in order to avoid persistence or recurrence of symptoms. We describe a \ncase whereby the patient presented with complaints of thumb triggering in \nextension and associated disabling first dorsal compartment tendinosis. \nIntraoperatively, after supernumerary tendons were identified and addressed, the \nAPL was at risk for subluxation over a prominent fibroosseous ridge. Routine \nfirst dorsal compartment release alone may have failed to address all of this \npatient's pathology.",
"DeQuervain's disease of the first dorsal compartment of the wrist, is a common \nwrist pathology, pain results from resisted gliding of the abductor pollicis \nlongus and the extensor pollicis brevis tendon in the fibroosseous canal. \nManagement of resistant cases of DeQuervain's disease with failed conservative \ntreatment treated by surgical decompression yield satisfactory outcomes. A large \nnumber of patients being dissatisfied with the medical treatment, still present \nwith persistent pain and positive clinical finding. Surgical decompression is an \neffective method for the treatment of resistant cases of DeQuervain's disease. \nOutcome variables were measured by Scheller, Forget and Macey evaluation \ncriteria. Most of our patients were female 28(93.3%), housewife 17(56.7%) with \nmean age of 41.57 years, ranging from 25-60 years. Right sided involvement was \n20(66.7%) and Left sided involvement was 10(33.3%). Restricted movement of thumb \nin 30(100%) were the predominant symptoms. One (3.3%) patient develop chronic \ntenosynovitis, 1(3.3%) patient develop hypertrophic scar. There was no wound \ninfection in the follow-up period of 3-18 months. Satisfactory results were \nfound in 29(96.7%)."
] | ['https://meshb.nlm.nih.gov/record/ui?ui=D013710'] |
52fb20a32059c6d71c00005d | [
24079768,
20852673,
20223299
] | train | Which therapeutic interventions for sarcopenia have been applied | summary | The main bulk of experimental pharmacological interventions addressing the clinical problem of frailty have been focused on the use of hormones, as replacement therapy in subjects with low or normal circulating basal levels of the hormone. Results have been disappointing, except for the case of testosterone that have shown some benefits. The effectiveness of other potential therapeutic interventions (antioxidants, anti-inflammatory agents, nutritional supplements) appears to be limited or has not been explored in detail until now. | The main bulk of experimental pharmacological interventions addressing the clinical problem of frailty have been focused on the use of hormones, as replacement therapy in subjects with low or normal circulating basal levels of the hormone. Results have been disappointing, except for the case of testosterone that have shown some benefits. The effectiveness of other potential therapeutic interventions (antioxidants, anti-inflammatory agents, nutritional supplements) appears to be limited or has not been explored in detail until now. | [
"Frailty has emerged as one of the most relevant clinical syndromes in older \npatients. This term relates to the loss of functional reserve that can occur in \nsome older people following exposure to one or more low-intensity stressors \nplacing them at high risk for developing a number of adverse outcomes such as \ndisability, falls, hospitalization and death. Frailty is the outcome of two \ncombined effects: the ageing process and other superimposed injuries like \nchronic disease or, indeed, psychological and social stressors. The mechanisms \nleading to frailty typically involve several systems: mainly hormones, oxidative \nstress, inflammation, immunity, and vascular system. One of the most outstanding \npillars of the frailty syndrome is the loss of muscle quantity and function, \nreferred to as sarcopenia. The main bulk of experimental pharmacological \ninterventions addressing the clinical problem of frailty have been focused on \nthe use of hormones, as replacement therapy in subjects with low or normal \ncirculating basal levels of the hormone. Results have been disappointing, except \nfor the case of testosterone that have shown some benefits. The effectiveness of \nother potential therapeutic interventions (antioxidants, anti-inflammatory \nagents, nutritional supplements) appears to be limited or has not been explored \nin detail until now. In conclusion, there is an available path to prevent the \ndevelopment of disability in older people through the treatment of frailty, its \nmain risk factor. Aditional research and further experimental testing will help \nto identify new targets and help to make this journey successful.",
"Sarcopenia is the loss of skeletal muscle mass and function with aging. Although \nthe term sarcopenia was first coined in 1989, its etiology is still poorly \nunderstood. Moreover, a consensus for defining sarcopenia continues to elude us. \nSarcopenic changes in the muscle include losses in muscle fiber quantity and \nquality, alpha-motor neurons, protein synthesis rates, and anabolic and sex \nhormone production. Other factors include basal metabolic rate, increased \nprotein dietary requirements, and chronic inflammation secondary to age-related \nchanges in cytokines and oxidative stress. These changes lead to decreased \noverall physical functioning, increased frailty, falls risk, and ultimately the \nloss of independent living. Because the intertwining relationships of these \nfactors are complex, effective treatment options are still under investigation. \nThe published data on sarcopenia are vast, and this review is not intended to be \nexhaustive. The aim of this review is to provide an update on the current \nknowledge of the definition, etiology, consequences, and current clinical trials \nthat may help address this pressing public health problem for our aging \npopulations.",
"Frailty is a geriatric syndrome characterized by muscle weakness, sarcopenia, \nand fatigue, and is associated with several adverse health outcomes, including \ndisability. Design of therapeutic interventions for geriatric frailty has been \nchallenging and may be because of inadequate understanding of its biological \nunderpinnings. Carnitine is important for energy production in skeletal muscles \nand there seems to be a negative correlation between advancing age and muscle \ncarnitine levels. Carnitine deficiency may therefore contribute to geriatric \nfrailty. Age-associated carnitine deficiency from a variety of etiologies, \nincluding organic cation transporter (OCTN2) mutation and carnitine \npalmitoyltransferase II (CPT) deficiency, may potentially explain the \nrelationship between carnitine-associated mitochondrial dysfunction and \ngeriatric frailty. Development of therapeutic agents capable of prevention or \nreversal of carnitine deficiency in older adults may minimize the occurrence of \nfrailty in geriatric populations."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016033', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D055948'] |
52ece29f98d023950500002c | [
8115332,
21874823,
18940949,
1422238,
8475937,
22986150,
19541799,
17684393,
9350446,
1580595,
8594618,
21825978,
12946875,
9092799,
2885829,
7833674,
24170966,
23392090,
8421095,
21459689,
17040361,
21468521,
10687857,
17132274,
17161330,
18334584,
17574009
] | train | Which thyroid hormone transporter is implicated in thyroid hormone resistance syndrome? | factoid | thyroid hormone transporter MCT8 is implicated in thyroid hormone resistance syndrome | 8 | [
"Although rare, thyroid hormone resistance syndrome should be suspected on a \nbiological profile combining high thyroid hormone and non-suppressed TSH plasma \nlevels. Resistance to thyroid hormone can be classified into 3 forms: \ngeneralized, pituitary and peripheral, all three showing tissue resistance \nheterogeneity from one person to another, and from one tissue to another in the \nsame subject. In the generalized and pituitary forms, thyroid hormone levels are \nhigh with paradoxically normal or increased TSH levels. The TRH test still \nstimulates TSH secretion, and only the highest doses of T3 successfully suppress \nTSH secretion. In the generalized form, euthyroidism is usual, whereas in the \npituitary form hyperthyroidism requires treatment in order to lower TSH \nsecretion. In the peripheral form, various symptoms of thyroid hormone \ndeficiency may be observed, contrasting with normal T3, T4 and TSH serum levels, \nand requiring supraphysiological doses of T3 for correction. In most cases, \nfamilial occurrence can be evidenced, with an autosomal dominant or sometimes \nrecessive mode of inheritance. Genetic analysis has identified, in the \ngeneralized form, more than 10 mutations of the thyroid hormone receptor beta \ngene, all resulting in an alteration in the T3 binding domain of the receptor. \nIn the autosomal dominant form, tissue resistance may result from a \"dominant \ninhibitory effect\" of the normal receptor function by the mutant receptor. All \nthese thyroid hormone resistance syndromes constitute exceptional models for \nstudying the mechanisms of action of thyroid hormones. Simultaneous observations \nof the mutated receptors with various clinical and biological phenotypes should \nfurther our understanding of thyroid hormone receptor function.",
"Laboratory findings can definitely help the patients not to enter into status, \nwhere the damage might be happen due to a miss-diagnosis based on clinical \nassessment alone. The secondary disease accompanied with thyroid patients should \nalso carefully check out due to the interference which some diseases can cause \nin the amount of serum thyroid hormone, particularly the free thyroxin. The \ndilemma over thyroid clinical diagnosis occur due to variation on serum thyroid \nhormone which initiated by other non-thyroidal disorders which can play an \nimportant roles in metabolic disorders of thyroid hormone due to the alteration \nwhich occur on the serum level of thyroid hormone transporter proteins. The \nmajority of serum thyroid hormones of up to 95-99% are bound to the carrier \nproteins mainly to Thyroxin-Binding Globulins (TBG), some transthyretin already \nknown as pre-albumin and albumin which are all synthesis in the liver and any \nmodification which alter their production may alter the status of thyroid \nhormones. It seems TBG, transthyretin and albumin carries 75, 20, 5% of thyroid \nhormones within blood circulation, respectively. The dilemma facing the thyroid \nhormones following disruption of thyroid hormone transporter protein synthesis \noriginate from this fact that any alteration of these protein contribute to the \nalteration of total thyroid and free serum thyroid hormones which are in fact \nthe biologically active form of thyroid hormones. The subsequent of latter \nimplication result in miss-understanding and miss-diagnosis of thyroid function \ntests, with possible wrongly thyroid clinical care, followed by undesired \ntherapy of otherwise healthy thyroid.",
"Thyroid hormone resistance (THR) is a rare syndrome of reduced end organ \nsensitivity. Patients with THR have elevated serum free thyroxine (FT4), free \ntriiodothyronine (FT3), but normal or slightly elevated serum thyrotropin \nvalues. The characteristic clinical feature is goitre without symptoms and \nmetabolic consequences of thyroid hormone excess. THR can be classified on the \nbasis of tissue resistance into pituitary, peripheral or generalised (both \npituitary and peripheral) types. Mutations in the TRbeta gene, cell membrane \ntransporter and genes controlling intracellular metabolism of thyroid hormone \nhave been implicated. THR is differentiated from thyroid stimulating hormone \n(TSH) secreting pituitary adenoma by history of THR in the family. No specific \ntreatment is often required for THR; patients with features of hypo- or \nhyperthyroidism are appropriately treated with levo-triiodothyronine (L-T3), \nlevo-thyroxine (L-T4), dextro-thyroxine(D-T4) or 3,3,5 triiodo-thyroacetic acid \n(TRIAC). The diagnosis helps in appropriate genetic counselling of the family.",
"Variations in major thyroid hormone transport proteins may be inherited or \nacquired and may be associated with changes in serum concentration of the \nproteins or their affinity for thyroid hormones. These variations most \nfrequently involve thyroxine-binding globulin (TBG), but changes in \ntransthyretin and albumin are also observed. The consequent alteration of \nthyroid hormone-binding capacity in serum is associated with variations in total \nthyroid hormone concentration. Increased serum total thyroid hormone levels are \nfound in subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia, \nand transthyretin-associated hyperthyroxinemia. Conversely, diminished serum \nthyroid hormone values are observed in subjects with TBG deficiency, and \ndecreased concentration or affinity of transthyretin and albumin is not \nassociated with variations in serum concentrations of thyroid hormones. The \ntransport protein-associated variations in serum total thyroid hormone \nconcentrations do not reflect a change in thyroid status. Euthyroidism can be \neasily established in subjects with transport protein abnormalities by the \nnormal free thyroid hormone and TSH concentrations. It is, however, crucial to \nselect methods for free thyroid hormone measurement that are not affected by \nabnormalities of transport proteins. Some assays, such as the analog method, \noften provide artifactual and misleading results, which may lead to \ninappropriate and even detrimental treatments. The evolutionary advantage of TBG \n(and albumin) in terms of thyroid homeostasis still remains to be elucidated.",
"The thyroid hormone resistance syndromes are disorders in which the body's \ntissues are resistant to the effects of thyroid hormone. Generalized resistance \nto thyroid hormone (GRTH) is characterized by resistance in the pituitary gland \nand in most or all of the peripheral tissues. Affected individuals have elevated \nserum thyroid hormone levels and inappropriately normal or elevated \nthyroid-stimulating hormone (TSH) but are usually clinically euthyroid and \nrequire no treatment. Selective pituitary resistance to thyroid hormone (PRTH) \nis characterized by resistance in the pituitary gland but not in peripheral \ntissues. Patients have elevated serum thyroid hormone levels and normal or \nelevated TSH levels and are clinically thyrotoxic. Therapy is usually necessary, \nbut current choices are not completely satisfactory. Selective peripheral \nresistance to thyroid hormone (PerRTH) is characterized by resistance in \nperipheral tissues but not in the pituitary. The only patient thus far described \nhad normal serum thyroid hormone and TSH levels but was clinically hypothyroid \nand improved with thyroid hormone administration. All of these disorders are \nprobably more common than is generally recognized and are often misdiagnosed and \ninappropriately treated. GRTH, in most cases studied, results from a mutation in \nthe thyroid hormone receptor beta gene causing an amino acid substitution in or \na partial or complete deletion of the thyroid hormone-binding domain of the \nreceptor. The causes of PRTH and PerRTH remain to be determined.",
"BACKGROUND: Six known steps are required for the circulating thyroid hormone \n(TH) to exert its action on target tissues. For three of these steps, human \nmutations and distinct phenotypes have been identified.\nSCOPE OF REVIEW: The clinical, laboratory, genetic and molecular characteristics \nof these three defects of TH action are the subject of this review. The first \ndefect, recognized 45years ago, produces resistance to TH and carries the \nacronym, RTH. In the majority of cases it is caused by TH receptor β gene \nmutations. It has been found in over 3000 individuals belonging to approximately \n1000 families. Two relatively novel syndromes presenting reduced sensitivity to \nTH involve membrane transport and metabolism of TH. One of them, caused by \nmutations in the TH cell-membrane transporter MCT8, produces severe psychomotor \ndefects. It has been identified in more than 170 males from 90 families. A \ndefect of the intracellular metabolism of TH in 10 individuals from 8 families \nis caused by mutations in the SECISBP2 gene required for the synthesis of \nselenoproteins, including TH deiodinases.\nMAJOR CONCLUSIONS: Defects at different steps along the pathway leading to TH \naction at cellular level can manifest as reduced sensitivity to TH.\nGENERAL SIGNIFICANCE: Knowledge of the molecular mechanisms involved in TH \naction allows the recognition of the phenotypes caused by defects of TH action. \nOnce previously known defects have been ruled out, new molecular defects could \nbe sought, thus opening the avenue for novel insights in thyroid physiology. \nThis article is part of a Special Issue entitled Thyroid hormone signaling.",
"Thyroid hormone is a pleiotropic hormone with widespread biological actions. For \ninstance, adequate levels of thyroid hormone are critical for the development of \ndifferent tissues such as the central nervous system, but are also essential for \nthe regulation of metabolic processes throughout life. The biological activity \nof thyroid hormone depends not only on serum thyroid hormone levels, but is also \nregulated at the tissue level by the expression and activity of deiodinases, \nwhich activate thyroid hormone or mediate its degradation. In addition, thyroid \nhormone transporters are necessary for the uptake of thyroid hormone into target \ntissues. With the discovery of monocarboxylate transporter 8 (MCT8) as a \nspecific thyroid hormone transporter and the finding that mutations in this \ntransporter lead to a syndrome of severe psychomotor retardation and elevated \nserum 3,3',5-tri-iodothyronine levels known as the Allan-Herndon-Dudley \nsyndrome, the interest in this area of research has greatly increased. In this \nreview, we will focus on the molecular aspects of thyroid hormone transporters, \nincluding MCT8, MCT10, organic anion transporting polypeptides, and the effects \nof genetic variation in these transporters.",
"In in vitro experiments, active transport of thyroid hormones had been \nrepeatedly demonstrated. The membrane transporters for thyroid hormones which \nhave been identified include the organic anion transporting polypeptide, \nheterodimeric amino acid transporters and the monocarboxylate transporters (MCT) \nwhich are the focus of this chapter. The gene encoding MCT8 which was identified \nas a specific thyroid hormone transporter is located on chromosome Xq13.2. The \nexpression pattern of MCT8 indicates that MCT8 plays an important role in the \ndevelopment of the central nervous system by transporting thyroid hormone into \nneurons as its main target cells. Mutational analysis of the MCT8 gene revealed \nmutations or deletions in the MCT8 gene in unrelated male patients with severe \npsychomotor retardation and biochemical findings consistent with thyroid hormone \nresistance. Indeed, thyroid function tests in patients with MCT8 mutations \ndemonstrated marked elevations of serum T3 (in the thyrotoxic range), a \nsignificant decrease in serum T4 or fT4 and normal to elevated TSH levels.",
"Resistance to thyroid hormone (RTH) is usually dominantly inherited and is \ncharacterized by elevated free thyroid hormones in the serum and failure to \nsuppress pituitary thyroid stimulating hormone (TSH) secretion with variable \nrefractoriness to hormone action in peripheral tissues. Two major forms of the \ndisorder are recognized: asymptomatic individuals with generalized resistance \n(GRTH) and patients with thyrotoxic features, suggesting predominant pituitary \nresistance (PRTH). Molecular genetic analyses indicate that both GRTH and PRTH \nare associated with diverse mutations in the thyroid hormone receptor beta gene, \nwhich localize to three regions in the hormone binding domain of the receptor. \nIn addition to being functionally impaired, the mutant receptors are also able \nto inhibit their wild-type counterparts in a dominant negative manner. \nRecognized features of RTH include failure to thrive, growth retardation and \nattention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic \ncardiac symptoms in adults. The pathogenesis of variable tissue resistance is \nnot fully understood but may be related to the differing tissue distributions of \na and b thyroid hormone receptors and variable dominant negative activity of \nmutant receptors on different target genes.",
"Generalized resistance to thyroid hormone (GRTH) encompasses a heterogeneous \ngroup of conditions characterized by reduced responses of target tissues to \nthyroid hormone due to defects at the site of hormone action. In the majority of \npatients, GRTH is inherited as a dominant trait associated with mutations in the \nhormone-binding domain of the thyroid hormone receptor. GRTH serves as a \nprototype of other resistance syndromes for hormones that act via nuclear \nreceptors.",
"Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear \nthyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are \ntranscription factors that act by altering patterns of gene expression. \nResistance to thyroid hormone (RTH) is a rare disorder caused by mutations in \nthe TR beta gene. Biochemically, the syndrome is defined by elevated circulating \nlevels of free thyroid hormones due to reduced target tissue responsiveness and \nnormal, or elevated, levels of thyroid-stimulating hormone (TSH). This \n\"inappropriate\" TSH elevation contrasts with the situation in hyperthyroidism, \nwhere the pituitary secretion of TSH is suppressed. Patients with RTH usually \npresent with goiter and an euthyroid or mildly hypothyroid metabolic state. \nThus, pituitary resistance results in hypersecretion of TSH, which compensates, \nat least in part, for hormone resistance in peripheral tissues. Despite this \ncompensation, clinical effects of RTH can include short stature, delayed bone \nmaturation, hyperactivity, learning disabilities, and hearing defects, as well \nas variable features of hyper- and hypothyroidism. With the exception of a \nsingle sibship, which harbored a deletion of the entire coding sequence of the \nTR beta gene and a recessive pattern of inheritance, all other cases of RTH have \nbeen inherited in an autosomal dominant manner or have been de novo heterozygous \nmutations of the TR beta gene. The dominant pattern of inheritance is explained \nby the functional properties of the mutant receptors which act in a dominant \nnegative manner to block the activity of normal TR alpha and TR beta receptors. \nNow that a large number of different RTH mutations have been identified, it is \nstriking that the mutations are clustered within restricted domains in the \ncarboxyterminal region of the receptor. Mutations in these regions have been \nshown to preserve critical receptor functions such as dimerization and DNA \nbinding, while inactivating other activites such as T3 binding and \ntranscriptional activation. The examination of patients with RTH and their \nmutated receptors has provided important insights into the mechanisms of thyroid \nhormone action, the structure-function relationship of the receptors, and the \nmolecular mechanisms of dominant negative activity.",
"PURPOSE OF REVIEW: To discuss the recent advances on thyroid hormone transport \nin the brain. A special attention is paid to the X-linked thyroid hormone cell \ntransport (THCT) defect (also known as the Allan-Herndon-Dudley syndrome), \ncaused by mutations of the specific thyroid hormone transporter MCT8 gene.\nRECENT FINDINGS: MCT8 is involved in thyroid hormone transport in the brain. MRI \nof patients with THCT defect showed myelination delays, probably related to \nimpaired thyroid hormone action on oligodendrocytes. MCT8 is also expressed in \nthe thyroid and has an important role in thyroid hormone secretion. The altered \ncirculating concentrations of thyroid hormone in the patients are partly because \nof impaired secretion and altered peripheral metabolism. Increased deiodinase \nactivity is important in the pathophysiology of the syndrome. High D1 activity \nin liver and kidney increases T4 and rT3 deiodination, and contributes to the \nincreased serum T3. High D2 activity in the brain contributes to compensate the \ndeficient T3 transport by increasing local T3 production.\nSUMMARY: Patients with suspected X-linked leukoencephalopathy should be screened \nfor MCT8 gene mutations. Research on the brain pathophysiology of the THCT \ndefect should focus on the specific role of Mct8 on oligodendrocytes and \nmyelination.",
"Resistance to thyroid hormone (RTH) is a syndrome in which patients have raised \nserum thyroid hormone (TH) levels and raised or inappropriately normal \nthyrotropin (TSH) levels. In general, patients exhibit TH resistance in the \npituitary and peripheral tissues. Novel techniques and genetically engineered \nmouse model systems have increased our understanding of thyroid hormone receptor \n(TR) action, and shed new light on the underlying molecular mechanisms for RTH. \nIn particular, we are learning how mutant TRs from RTH patients can block \nwild-type TR function, with consequent effects in various tissues and cells. \nThis dominant-negative activity has important implications for other \nhormone-resistant conditions and in hormone-sensitive tumors. This article \nexamines the molecular basis of RTH.",
"Nuclear hormone receptors are hormone-regulated transcription factors that play \ncritical roles in chordate development and homeostasis. Aberrant nuclear hormone \nreceptors have been implicated as causal agents in a number of endocrine and \nneoplastic diseases. The syndrome of Resistance to Thyroid Hormone (RTH) is a \nhuman genetic disease characterized by an impaired physiological response to \nthyroid hormone. RTH is associated with diverse mutations in the thyroid hormone \nreceptor beta-gene. The resulting mutant receptors function as dominant \nnegatives, interfering with the actions of normal thyroid hormone receptors \ncoexpressed in the same cells. We report here that RTH receptors interact \naberrantly with a newly recognized family of transcriptional corepressors \nvariously denoted as nuclear receptor corepressor (N-CoR), retinoid X receptor \ninteracting protein-13 (RIP-13), silencing mediator for retinoid and thyroid \nhormone receptors (SMRT), and thyroid hormone receptor-associating cofactor \n(TRAC). All RTH receptors tested exhibit an impaired ability to dissociate from \ncorepressors in the presence of thyroid hormone. Two of the RTH mutations \nuncouple corepressor dissociation from hormone binding; two additional RTH \nmutants exhibit an unusually strong interaction with corepressor under all \nhormone conditions tested. Finally, artificial mutants that abolish corepressor \nbinding abrogate the dominant negative activity of RTH mutants. We suggest that \nan altered corepressor interaction is likely to play a critical role in the \ndominant negative potency of RTH mutants and may contribute to the variable \nphenotype in this disorder.",
"Known since 1967 and usually familial, the syndrome of tissue resistance to \nthyroid hormones may take one of two different forms, depending on the receptors \ninvolved. When resistance affects both peripheral and pituitary receptors, \nplasma thyroid hormone levels are high despite the lack of thyrotoxicosis, \nthyroxine and triiodothyronine are ineffective, even in high dosage, and plasma \nTSH increases to explode under TRH. When resistance only affects pituitary \nreceptors, there is moderate thyrotoxicosis with paradoxical and inappropriate \nTSH increase. Contrary to expectations, nuclear receptors to triiodothyronine \nare perturbed in only a few cases. Reduction of thyrotropic hyperfunction, which \nis the primary purpose of treatment, can be achieved with D-forms of thyroid \nhormones or with somatostatin and its derivatives.",
"Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by \nreduced tissue responsiveness to thyroid hormone. Subjects have elevated serum \nthyroid hormone levels in association with a nonsuppressed TSH. Goiter and \nthyroid test abnormalities have most often led to further investigation, \nunderscoring the paucity of specific clinical manifestations of RTH. \nHypothyroidism has been considered when growth or mental retardation was the \npresenting symptom and thyrotoxicosis when dealing with attention deficit or \nhyperactivity. Failure to recognize the inappropriate persistence of TSH \nsecretion, in spite of elevated thyroid hormone levels, has commonly resulted in \nerroneous diagnosis leading to treatment aimed to normalize the thyroid hormone \nlevel. More than 400 subjects with this syndrome have been identified. The mode \nof inheritance appears to be autosomal dominant in the majority of families. It \nhas long been suspected that RTH is most likely caused by an abnormal thyroid \nhormone receptor (TR), but this hypothesis could not be directly tested until \nthe isolation of two TR genes, TR alpha and TR beta, located in chromosomes 17 \nand 3, respectively. TR beta gene mutations have been recently identified in 68 \nfamilies with RTH. All mutations are located in the T3-binding domain, \nstraddling the putative TR-dimerization region. Mutant TRs exhibit \nhormone-binding impairment, the degree of which does not correlate with the \nseverity of clinical manifestations. This finding, and the fact that \nheterozygous subjects with complete TR deletion are not affected, while those \nwith point mutations are, indicated that interactions of the mutant TRs with \nnormal TRs and with other factors, are responsible for the dominant inheritance \nof RTH and its clinical heterogeneity.(ABSTRACT TRUNCATED AT 250 WORDS)",
"Allan-Herndon-Dudley Syndrome (AHDS), an X linked condition, is characterized by \ncongenital hypotonia that progresses to spasticity with severe psychomotor \ndelays, in combination with altered thyroid hormone levels, in particular, high \nserum T3 levels. Recently, this disease was proved to be caused by mutations in \nSLC16A2 coding for the monocarboxylate thyroid hormone transporter 8 (MCT8). \nHere we describe a 26-year -old Japanese patient with AHDS who had deletion of \nexon 3 of SLC16A2.",
"Cellular entry is an important step preceding intracellular metabolism and \naction of thyroid hormone (TH). Transport of TH across the plasma membrane does \nnot take place by simple diffusion but requires transporter proteins. One of the \nmost effective and specific TH transporters identified to date is \nmonocarboxylate transporter 8 (MCT8), the gene of which is located on the X \nchromosome. Although MCT8 is expressed in many tissues, its function appears to \nbe most critical in the brain. Hemizygous MCT8 mutations in males cause severe \npsychomotor retardation, known as the Allan-Herndon-Dudley syndrome (AHDS), and \nabnormal serum TH levels. AHDS thus represents a type of TH resistance caused by \na defect in cellular TH transport.",
"Generalized resistance to thyroid hormone (GRTH), a syndrome of inherited tissue \nhyposensitivity to thyroid hormone, is linked to thyroid hormone receptor (TR) \nmutations. A typical feature of GRTH is variable severity of organ involvement \namong families that, surprisingly, does not correlate with the degree of \nT3-binding impairment of the corresponding in vitro synthesized mutant TRs. \nFurthermore, variations in the clinical severity among family members harboring \nidentical TR beta mutations have been reported. We compared serum levels of \nthyroid hormones that maintained a normal TSH in members of a large family with \nGRTH divided in three groups: Group A, 8 affected subjects with a mutation \nreplacing arginine-320 with a histidine in the T3-binding domain of TR beta; \nGroup B, 11 first degree relatives (sibs and children of affected subjects) with \nno TR beta mutation; Group C, 16 controls related by marriage. TSH values were \nnot different among the three groups. As expected, total and free T4 and T3, and \nrT3 levels were significantly higher in Group A vs Groups B and C. However, with \nthe exception of T3, the same tests were also significantly higher in Group B vs \nGroup C. The latter differences are not due to thyroid hormone transport in \nserum since TBG concentrations were not different. It is postulated that genetic \nvariability of factors that contribute to the action of thyroid hormone modulate \nthe phenotype of GRTH associated with TR beta mutations.",
"Thyroid hormone resistance syndromes are a group of genetic conditions \ncharacterized by decreased tissue sensitivity to thyroid hormones. Three \nsyndromes, in which resistance to hormone action is respectively due to \nmutations in the gene encoding for thyroid hormone receptor TRβ, impaired T4 and \nT3 transport, and impaired conversion of T4 to T3 mediated by deiodinases. An \nupdated review of each of these forms of resistance is provided, and their \npathogenetic mechanisms and clinical approaches are discussed.",
"The finding of increased thyroxine (T4) and tri-iodothyronine (T3) levels in a \npatient with normal or increased thyroid-stimulating hormone is unexpected and \npresents a differential diagnosis between a thyroid-stimulating \nhormone-secreting pituitary adenoma, generalized resistance to thyroid hormone \n(RTH) and laboratory artefact. Without careful clinical and biochemical \nevaluation, errors may occur in patient diagnosis and treatment. In the case of \nRTH, mutation of the thyroid hormone receptor beta gene results in generalized \ntissue resistance to thyroid hormone. As the pituitary gland shares in this \ntissue resistance, euthyroidism with a normal thyroid-stimulating hormone is \nusually maintained by increased thyroid hormones. To date, we have identified \neight pedigrees in New Zealand with mutations in the thyroid hormone receptor \nbeta gene, including two novel mutations. Mutational analysis of the thyroid \nhormone receptor beta gene allows definitive diagnosis of RTH, potentially \navoiding the need for protracted and expensive pituitary function testing and \nimaging. Mutational analysis also enables family screening and may help to avoid \npotential misdiagnosis and inappropriate treatment.",
"MCT8 is a cellular transporter of thyroid hormones important in their action and \nmetabolization. We report a male patient with the novel inactivating mutation \n630insG in the coding region in exon 1 of MCT8. He was characterized clinically \nby severe neurologic impairment (initially with global hypotonia, later evolving \nwith generalized hypertonia), normal growth during infancy, reduced weight gain, \nand absence of typical signs and symptoms of hypothyroidism, while the \nlaboratory evaluation disclosed elevated T3, low total and free T4, and mildly \nelevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone \nprofile but was not able to alter the clinical picture of the patient. These \ndata reinforce the concept that the role of MCT8 is tissue-dependent: while \nneurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and \nliver are less dependent on MCT8 and, therefore, may suffer the consequences of \nthe exposition to high serum T3 levels.",
"Thyroid hormone receptors (T3Rs) both repress and activate gene transcription by \ninteracting with auxiliary factors denoted corepressors and coactivators. \nResistance to thyroid hormone (RTH) syndrome in humans is manifested as a \nfailure to respond properly to elevated circulating thyroid hormone. RTH \nsyndrome has been mapped to T3Rbeta mutations that alter the transcriptional \nproperties of the receptor, resulting in a dominant negative phenotype. We \nreport here a characterization of a series of RTH mutant T3Rs that exhibit \nunusual interactions with corepressor. Two mutations in receptor helix 11 \n(delta430, delta432) greatly enhance the ability of the mutant receptors to bind \nto corepressor. A distinct mutation, V264D, in an 'omega loop' region of the \nreceptor, impairs corepressor release but does not fully eliminate the ability \nto recruit coactivator. These mutations reveal novel determinants that regulate \nthe interaction of the T3R with important ancillary cofactors, and that are \ndisrupted in a human endocrine disease.",
"Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited \nsyndrome of reduced end-organ responsiveness to thyroid hormone. Patients with \nRTH have elevated serum free thyroxine (FT4) and free triiodothyronine (FT3) \nconcentrations and normal or slightly elevated serum thyroid stimulating hormone \n(TSH) level. Despite a variable clinical presentation, the common characteristic \nclinical features are goitre but an absence of the usual symptoms and metabolic \nconsequences of thyroid hormone excess. Patients with RTH can be classified on \nclinical grounds alone into either generalized resistance (GRTH), pituitary \nresistance (PRTH) or combined. Mutations in the thyroid hormone receptor (TR) \nbeta gene are responsible for RTH and 122 different mutations have now been \nidentified belonging to 300 families. With the exception of one family found to \nhave complete deletion of the TRbeta gene, all others have been demonstrated to \nhave minor alterations at the DNA level. The differential diagnosis includes a \nTSH-secreting pituitary adenoma and the presence of endogenous antibodies \ndirected against thyroxine (T4) and triiodothyronine (T3). Failure to \ndifferentiate RTH from primary thyrotoxicosis has resulted in the inappropriate \ntreatment of nearly one-third of patients. Although occasionally desirable, no \nspecific treatment is available for RTH; however, the diagnosis allows \nappropriate genetic counselling.",
"Forty years have elapsed since the first description of a syndrome of resistance \nin the hypothalamic-pituitary-thyroid axis, i.e., resistance to thyroid hormone \naction. In the last two decades many other types of resistance have been \ndiscovered, including resistance to the action of thyrotropin-releasing hormone \n(TRH), of thyroid-stimulating hormone (TSH), and of thyroid hormones (THs); the \nlatter can be due not only to thyroid hormone receptor defects but also to \nalteration in genes encoding TH-specific transporters or components involved in \nmetabolic pathways of THs. Moreover, alteration in genes encoding for second \nmessengers may cause forms of resistance other than those due to receptor \nmutations, the most important one being that of an inactivating mutation in the \nG-protein alpha-subunit leading to TSH resistance in the setting of \npseudohypoparathyroidism type 1a. Recognition of these rare thyroid disorders is \nof great importance not only for informed genetic counselling but also for \navoiding diagnostic mistakes that may lead to incorrect and potentially \ndangerous treatments.",
"CONTEXT: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a \ndistinct X-linked phenotype of severe psychomotor retardation and consistently \nelevated T(3) levels. Lack of MCT8 transport of T(3) in neurons could explain \nthe neurological phenotype.\nOBJECTIVE: Our objective was to determine whether the high T(3) levels could \nalso contribute to some critical features observed in these patients.\nRESULTS: A 16-yr-old boy with severe psychomotor retardation and hypotonia was \nhospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had \ntachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated \nserum free T(3) (FT(3)) level (11.3 pmol/liter), without FT(4) and TSH \nabnormalities. A missense mutation of the MCT8 gene was present. Oral \noverfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) \nand then PTU plus levothyroxine (LT(4)) was tested. After PTU (200 mg/d), serum \nFT(4) was undetectable, FT(3) was reduced (3.1 pmol/liter) with high TSH levels \n(50.1 mU/liter). Serum SHBG levels were reduced (72 nmol/liter). While PTU \nprescription was continued, high LT(4) doses (100 microg/d) were needed to \nnormalize serum TSH levels (3.18 mU/liter). At that time, serum FT(4) was normal \n(16.4 pmol/liter), and FT(3) was slightly high (6.6 pmol/liter). Tachycardia was \nabated (84 beats/min), weight gain was 3 kg in 1 yr, and SHBG was 102 \nnmol/liter.\nCONCLUSIONS: 1) When thyroid hormone production was reduced by PTU, high doses \nof LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that \nmutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T(3) \nlevels might exhibit some deleterious effects on adipose, hepatic, and cardiac \nlevels. 3) PTU plus LT(4) could be an effective therapy to reduce general \nadverse features, unfortunately without benefit on the psychomotor retardation.",
"At least six major steps are required for secreted thyroid hormone (TH) to exert \nits action on target tissues. Mutations interfering with three of these steps \nhave been so far identified. The first recognized defect, which causes \nresistance to TH, involves the TH receptor beta gene and has been given the \nacronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 \naffected subjects, from 339 families, have been identified. The gene defect \nremains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced \nsensitivity to TH were recently identified. One, producing severe psychomotor \ndefects in > 100 males from 26 families, is caused by mutations in the \ncell-membrane transporter of TH, MCT8; the second, affecting the intracellular \nmetabolism of TH in four individuals from two families, is caused by mutations \nin the SECISBP2 gene, which is required for the synthesis of selenoproteins, \nincluding TH deiodinases."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D013963', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0009914', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014284', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D011815', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D037021', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D060467', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018382', 'http://www.disease-ontology.org/api/metadata/DOID:11633', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014186', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D037042'] |
5c7d5ae9d774d04240000010 | [
29734265,
28756250
] | train | Which tissue secretes vaspin? | factoid | Visceral adipose tissue-derived serine protease inhibitor (Vaspin) is an adipocytokine that has been shown to exert anti-inflammatory effects and inhibits apoptosis under diabetic conditions. | Adipose Tissue | [
"Visceral adipose tissue-derived serine protease inhibitor (Vaspin) is an \nadipocytokine that has been shown to exert anti-inflammatory effects and \ninhibits apoptosis under diabetic conditions. This study was designed to \ninvestigate the impact of vaspin on autophagy in tumor necrosis factor \n(TNF)-α-induced injury in cardiomyocytes and its cardioprotective effects in the \npathogenesis of diabetic cardiomyopathy (DCM). H9C2 cells were treated with \nTNF-α with or without vaspin in vitro. Tumor necrosis factor-α treatment \ninhibited autophagy and promoted apoptosis in H9C2 cells after stimulating for \n24 hours. Pretreatment with vaspin significantly mitigated apoptosis induced by \nTNF-α partly because of augment effects of vaspin on autophagy as demonstrated \nby a higher ratio of LC3-II/LC3-I, higher expression of Beclin-1, and increased \nautophagosomes formation. Furthermore, the AKT agonist IGF-1 significantly \nreversed the effect of vaspin on autophagy. In vivo DCM model was also developed \nby treating rats with streptozotocin followed by intraperitoneal injection with \nvaspin. In DCM rats, upregulation of vaspin reversed cardiac dysfunction, as \nidentified by increased left ventricular ejection fractions and fractional \nshortening levels, a higher Em/Am ratio, and lower levels of TNF-α, lactate \ndehydrogenase, creatine kinase, and creatine kinase-myocardial isoenzyme. In \nconclusion, vaspin attenuated the TNF-α-induced apoptosis by promoting autophagy \nprobably through inhibiting the PI3K/AKT/mTOR pathway and further ameliorated \nthe cardiac dysfunction in DCM rats.",
"Vaspin expression is increased in white adipose tissue (WAT) of diet-induced \nobese mice and rats and is supposed to compensate HFD-induced inflammatory \nprocesses and insulin resistance in adipose tissue by counteracting \npro-inflammatory gene expression in obesity. Multiple studies have also \ndemonstrated strong anti-inflammatory effects in vascular and skin cells. Here, \nwe used vaspin treated 3T3-L1 murine adipocytes as well as 3T3-L1 cells with \nstable vaspin expression to investigate the effect of exogenous and endogenous \nvaspin on inflammatory processes and insulin signaling in adipocytes. Our stably \ntransfected cells secreted significant amounts of vaspin which was in the \nphysiological range of ∼0.5 ng/ml in cell supernatants. Adipocyte \ndifferentiation was not affected by vaspin as expression of adipogenic marker \ngenes as well as lipid accumulation after full differentiation was similar to \ncontrol cells. We found that IL-1β induced expression and secretion of \npro-inflammatory cytokines, such as IL-6, MCP1 and TNFα was significantly \nblunted in vaspin expressing 3T3-L1 cells. Treatment of 3T3-L1 cells with \nexogenous vaspin resulted in reduced cytokine-induced activation of the \nintracellular and pro-inflammatory NFκB signaling cascades (IKKα/β, IκB and \nNFκB). Moreover, endogenous vaspin positively affected insulin signaling by \nincreasing insulin-stimulated phosphorylation of the key mediator protein kinase \nB (AKT). Together, we demonstrate anti-inflammatory effects of vaspin in 3T3-L1 \nadipocytes as well as increased insulin signaling by endogenous expression or \nexogenous treatment. The results provide evidence for potent anti-inflammatory \naction of vaspin not only in vascular cells but also in adipose tissue."
] | nan |
5e80e449835f4e477700002c | [
24564768,
19333547,
15221932,
19014390
] | train | Which tissues express the ACE2 protein? | list | Abundant ACE2 immunostaining was found in lung, kidney, heart, and islets of pancreas, but not in hepatocytes | ['lung', 'kidney', 'heart', 'pancreas'] | [
"ACE2 (angiotensin converting enzyme 2) plays a critical role in the local tissue \nRAS (renin-angiotensin system) by hydrolysing the potent hypertensive and \nmitogenic peptide AngII (angiotensin II). Changes in the levels of ACE2 have \nbeen observed in a number of pathologies, including cardiovascular disease, but \nlittle is known of the mechanisms regulating its expression. In the present \nstudy, therefore, the potential role of miRNAs in the regulation of ACE2 \nexpression in primary human cardiac myofibroblasts was examined. Putative \nmiRNA-binding sites were identified in the 3'-UTR of the ACE2 transcript using \nonline prediction algorithms. Two of these, miR-200b and miR-421, were selected \nfor further analysis. A reporter system using the 3'-UTR of ACE2 fused to the \ncoding region of firefly luciferase was used to determine the functionality of \nthe identified binding sites in vitro. This identified miR-421, but not \nmiR-200b, as a potential regulator of ACE2. The ability of miR-421, an miRNA \nimplicated in the development of thrombosis, to down-regulate ACE2 expression \nwas subsequently confirmed by Western blot analysis of both primary cardiac \nmyofibroblasts and transformed cells transfected with a synthetic miR-421 \nprecursor. Real-time PCR analysis of miR-421 revealed widespread expression in \nhuman tissues. miR-421 levels in cardiac myofibroblasts showed significant \ninter-patient variability, in keeping with the variability of ACE2 expression we \nhave observed previously. In conclusion, the present study is the first to \ndemonstrate that ACE2 may be subject to post-transcriptional regulation and \nreveals a novel potential therapeutic target, miR-421, which could be exploited \nto modulate ACE2 expression in disease.",
"Multiple organ damage in severe acute respiratory syndrome (SARS) patients is \ncommon; however, the pathogenesis remains controversial. This study was to \ndetermine whether the damage was correlated with expression of the SARS \ncoronavirus receptor, angiotensin converting enzyme 2 (ACE2), in different \norgans, especially in the endocrine tissues of the pancreas, and to elucidate \nthe pathogenesis of glucose intolerance in SARS patients. The effect of clinical \nvariables on survival was estimated in 135 SARS patients who died, 385 \nhospitalized SARS patients who survived, and 19 patients with non-SARS \npneumonia. A total of 39 SARS patients who had no previous diabetes and received \nno steroid treatment were compared to 39 matched healthy siblings during a \n3-year follow-up period. The pattern of SARS coronavirus receptor-ACE2 proteins \nin different human organs was also studied. Significant elevations in oxygen \nsaturation, serum creatinine, lactate dehydrogenase, creatine kinase MB \nisoenzyme, and fasting plasma glucose (FPG), but not in alanine transaminase \nwere predictors for death. Abundant ACE2 immunostaining was found in lung, \nkidney, heart, and islets of pancreas, but not in hepatocytes. Twenty of the 39 \nfollowed-up patients were diabetic during hospitalization. After 3 years, only \ntwo of these patients had diabetes. Compared with their non-SARS siblings, these \npatients exhibited no significant differences in FPG, postprandial glucose \n(PPG), and insulin levels. The organ involvements of SARS correlated with organ \nexpression of ACE2. The localization of ACE2 expression in the endocrine part of \nthe pancreas suggests that SARS coronavirus enters islets using ACE2 as its \nreceptor and damages islets causing acute diabetes.",
"Severe acute respiratory syndrome (SARS) is an emerging infectious disease \nassociated with a new coronavirus, SARS-CoV. Pulmonary involvement is the \ndominant clinical feature but extra-pulmonary manifestations are also common. \nFactors that account for the wide spectrum of organ system involvement and \ndisease severity are poorly understood and the pathogenesis of SARS-CoV \ninfection remains unclear. Angiotensin converting enzyme 2 (ACE2) has recently \nbeen identified as the functional cellular receptor for SARS-CoV. Studies of the \ntissue and cellular distribution of SARS-CoV, and ACE2 protein expression, \nreveal new insights into the pathogenesis of this deadly disease. ACE2 is \nexpressed at high level in the primary target cells of SARS-CoV, namely \npneumocytes and surface enterocytes of the small intestine. Despite the fact \nthat SARS-CoV can infect the lung and intestine, the tissue responses in these \ntwo organs are different. All other tissues and cell types expressing ACE2 may \nbe potential targets of SARS-CoV infection. Remarkably, endothelial cells, which \nexpress ACE2 to a high level, have not been shown to be infected by SARS-CoV. \nThere is also evidence that cell types without detectable ACE2 expression may \nalso be infected by the virus. Furthermore, studies in a new human cell culture \nmodel have indicated that the presence of ACE2 alone is not sufficient for \nmaintaining viral infection. Therefore, other virus receptors or co-receptors \nmay be required in different tissues. Moreover, the interaction between SARS-CoV \nand the immunological or lymphoid system remains to be defined. It is clear that \nwe are only at the dawn of our understanding of the pathogenesis of SARS. As our \nknowledge of the pathogenic mechanisms improves, a more rational approach to \ntherapeutic and vaccine development can be designed in order to combat this new \nand fatal human disease.",
"Angiotensin (Ang)-converting enzyme (ACE) 2 cleaves Ang-II into the vasodilator \npeptide Ang-(1-7), thus acting as a pivotal element in balancing the local \neffects of these peptides. ACE2 has been identified in various tissues and is \nsupposed to be a modulator of cardiovascular function. Decreases in ACE2 \nexpression and activity have been reported in models of hypertension, heart \nfailure, atherosclerosis, diabetic nephropathy and others. In addition, the \nexpression level and/or activity are affected by other renin-angiotensin system \ncomponents (e.g., ACE and AT1 receptors). Local inhibition or global deletion of \nbrain ACE2 induces a reduction in baroreflex sensitivity. Moreover, ACE2-null \nmice have been shown to exhibit either blood pressure or cardiac dysfunction \nphenotypes. On the other hand, over-expression of ACE2 exerts protective effects \nin local tissues, including the brain. In this review, we will first summarize \nthe major findings linking ACE2 to cardiovascular function in the periphery then \nfocus on recent discoveries related to ACE2 in the CNS. Finally, we will unveil \nnew tools designed to address the importance of central ACE2 in various \ndiseases, and discuss the potential for this carboxypeptidase as a new target in \nthe treatment of hypertension and other cardiovascular diseases."
] | nan |
5891c90949702f2e01000001 | [
15059815
] | train | Which tool employs self organizing maps for analyzing synonymous codon usage? | factoid | INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. | INCA | [
"INteractive Codon usage Analysis (INCA) provides an array of features useful in \nanalysis of synonymous codon usage in whole genomes. In addition to computing \ncodon frequencies and several usage indices, such as 'codon bias', effective Nc \nand CAI, the primary strength of INCA has numerous options for the interactive \ngraphical display of calculated values, thus allowing visual detection of \nvarious trends in codon usage. Finally, INCA includes a specific unsupervised \nneural network algorithm, the self-organizing map, used for gene clustering \naccording to the preferred utilization of codons.\nAVAILABILITY: INCA is available for the Win32 platform and is free of charge for \nacademic use. For details, visit the web page http://www.bioinfo-hr.org/inca or \ncontact the author directly.\nSUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a \nshort tutorial."
] | nan |
5e2b00bc76af173751000004 | [
29253077
] | train | Which tool exist for predicting drug synergy with deep learning? | factoid | Deep Learning has had an impact in many research areas by achieving new state-of-the-art model performance. DeepSynergy has been developed as a tool that uses chemical and genomic information as input information, a normalization strategy to account for input data heterogeneity, and conical layers to model drug synergies. | DeepSynergy | [
"MOTIVATION: While drug combination therapies are a well-established concept in \ncancer treatment, identifying novel synergistic combinations is challenging due \nto the size of combinatorial space. However, computational approaches have \nemerged as a time- and cost-efficient way to prioritize combinations to test, \nbased on recently available large-scale combination screening data. Recently, \nDeep Learning has had an impact in many research areas by achieving new \nstate-of-the-art model performance. However, Deep Learning has not yet been \napplied to drug synergy prediction, which is the approach we present here, \ntermed DeepSynergy. DeepSynergy uses chemical and genomic information as input \ninformation, a normalization strategy to account for input data heterogeneity, \nand conical layers to model drug synergies.\nRESULTS: DeepSynergy was compared to other machine learning methods such as \nGradient Boosting Machines, Random Forests, Support Vector Machines and Elastic \nNets on the largest publicly available synergy dataset with respect to mean \nsquared error. DeepSynergy significantly outperformed the other methods with an \nimprovement of 7.2% over the second best method at the prediction of novel drug \ncombinations within the space of explored drugs and cell lines. At this task, \nthe mean Pearson correlation coefficient between the measured and the predicted \nvalues of DeepSynergy was 0.73. Applying DeepSynergy for classification of these \nnovel drug combinations resulted in a high predictive performance of an AUC of \n0.90. Furthermore, we found that all compared methods exhibit low predictive \nperformance when extrapolating to unexplored drugs or cell lines, which we \nsuggest is due to limitations in the size and diversity of the dataset. We \nenvision that DeepSynergy could be a valuable tool for selecting novel \nsynergistic drug combinations.\nAVAILABILITY AND IMPLEMENTATION: DeepSynergy is available via \nwww.bioinf.jku.at/software/DeepSynergy.\nCONTACT: klambauer@bioinf.jku.at.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline."
] | nan |
5a6fa61ab750ff4455000060 | [
27366148
] | train | Which tool exists for microsatellite (SSR) loci detection and primer design? | factoid | Microsatellites are genomic sequences comprised of tandem repeats of short nucleotide motifs widely used as molecular markers in population genetics. FullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and primer design using genomic data from NGS assay. | FullSSR | [
"Microsatellites are genomic sequences comprised of tandem repeats of short \nnucleotide motifs widely used as molecular markers in population genetics. \nFullSSR is a new bioinformatic tool for microsatellite (SSR) loci detection and \nprimer design using genomic data from NGS assay. The software was tested with \n2000 sequences of Oryza sativa shotgun sequencing project from the National \nCenter of Biotechnology Information Trace Archive and with partial genome \nsequencing with ROCHE 454® from Caiman latirostris, Salvator merianae, Aegla \nplatensis, and Zilchiopsis collastinensis. FullSSR performance was compared \nagainst other similar SSR search programs. The results of the use of this kind \nof approach depend on the parameters set by the user. In addition, results can \nbe affected by the analyzed sequences because of differences among the genomes. \nFullSSR simplifies the detection of SSRs and primer design on a big data set. \nThe command line interface of FullSSR was intended to be used as part of genomic \nanalysis tools pipeline; however, it can be used as a stand-alone program \nbecause the results are easily interpreted for a nonexpert user."
] | ['https://meshb.nlm.nih.gov/record/ui?ui=D018895', 'https://meshb.nlm.nih.gov/record/ui?ui=D017931'] |
5c6aef167c78d69471000023 | [
29554207
] | train | Which tool has been developed for GPU-accelerated alignment of bisulfite-treated DNA sequences? | factoid | The alignment of bisulfite-treated DNA sequences (BS-seq reads) to a large genome involves a significant computational burden beyond that required to align non-bisulfite-treated reads. In the analysis of BS-seq data, this can present an important performance bottleneck that can be mitigated by appropriate algorithmic and software-engineering improvements. One strategy is to modify the read-alignment algorithms by integrating the logic related to BS-seq alignment, with the goal of making the software implementation amenable to optimizations that lead to higher speed and greater sensitivity than might otherwise be attainable. This strategy was evaluated using Arioc, a short-read aligner that uses GPU (general-purpose graphics processing unit) hardware to accelerate computationally-expensive programming logic. | Arioc | [
"MOTIVATION: The alignment of bisulfite-treated DNA sequences (BS-seq reads) to a \nlarge genome involves a significant computational burden beyond that required to \nalign non-bisulfite-treated reads. In the analysis of BS-seq data, this can \npresent an important performance bottleneck that can be mitigated by appropriate \nalgorithmic and software-engineering improvements. One strategy is to modify the \nread-alignment algorithms by integrating the logic related to BS-seq alignment, \nwith the goal of making the software implementation amenable to optimizations \nthat lead to higher speed and greater sensitivity than might otherwise be \nattainable.\nRESULTS: We evaluated this strategy using Arioc, a short-read aligner that uses \nGPU (general-purpose graphics processing unit) hardware to accelerate \ncomputationally-expensive programming logic. We integrated the BS-seq \ncomputational logic into both GPU and CPU code throughout the Arioc \nimplementation. We then carried out a read-by-read comparison of Arioc's \nreported alignments with the alignments reported by well-known CPU-based BS-seq \nread aligners. With simulated reads, Arioc's accuracy is equal to or better than \nthe other read aligners we evaluated. With human sequencing reads, Arioc's \nthroughput is at least 10 times faster than existing BS-seq aligners across a \nwide range of sensitivity settings.\nAVAILABILITY AND IMPLEMENTATION: The Arioc software is available for download at \nhttps://github.com/RWilton/Arioc. It is released under a BSD open-source \nlicense.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline."
] | nan |
62005c68c9dfcb9c09000017 | [
26854601
] | train | Which tool has been developed for annotation of Gα, Gβ and Gγ subunits of G-proteins? | factoid | GprotPRED is an online tool that uses profile Hidden Markov Models (pHMMs) and application to proteomes. The sensitivity and specificity for all pHMMs were equal to 100% with the exception of the Gβ case, where sensitivity equals to 100%, while specificity is 99.993%. | GprotPRED | [
"Heterotrimeric G-proteins form a major protein family, which participates in \nsignal transduction. They are composed of three subunits, Gα, Gβ and Gγ. The Gα \nsubunit is further divided in four distinct families Gs, Gi/o, Gq/11 and G12/13. \nThe goal of this work was to detect and classify members of the four distinct \nfamilies, plus the Gβ and the Gγ subunits of G-proteins from sequence alone. To \nachieve this purpose, six specific profile Hidden Markov Models (pHMMs) were \nbuilt and checked for their credibility. These models were then applied to ten \n(10) proteomes and were able to identify all known G-protein and classify them \ninto the distinct families. In a separate case study, the models were applied to \ntwenty seven (27) arthropod proteomes and were able to give more credible \nclassification in proteins with uncertain annotation and in some cases to detect \nnovel proteins. An online tool, GprotPRED, was developed that uses these six \npHMMs. The sensitivity and specificity for all pHMMs were equal to 100% with the \nexception of the Gβ case, where sensitivity equals to 100%, while specificity is \n99.993%. In contrast to Pfam's pHMM which detects Gα subunits in general, our \nmethod not only detects Gα subunits but also classifies them into the \nappropriate Gα-protein family and thus could become a useful tool for the \nannotation of G-proteins in newly discovered proteomes. GprotPRED online tool is \npublicly available for non-commercial use at \nhttp://bioinformatics.biol.uoa.gr/GprotPRED and, also, a standalone version of \nthe tool at https://github.com/vkostiou/GprotPRED."
] | nan |
5c59872b86df2b9174000017 | [
29096012
] | train | Which tool has been developed for coverage calculation for genomes? | factoid | Mosdepth is a command-line tool for rapidly calculating genome-wide sequencing coverage. It measures depth from BAM or CRAM files at either each nucleotide position in a genome or for sets of genomic regions. Genomic regions may be specified as either a BED file to evaluate coverage across capture regions, or as a fixed-size window as required for copy-number calling. Mosdepth uses a simple algorithm that is computationally efficient and enables it to quickly produce coverage summaries. | Mosdepth | [
"SUMMARY: Mosdepth is a new command-line tool for rapidly calculating genome-wide \nsequencing coverage. It measures depth from BAM or CRAM files at either each \nnucleotide position in a genome or for sets of genomic regions. Genomic regions \nmay be specified as either a BED file to evaluate coverage across capture \nregions, or as a fixed-size window as required for copy-number calling. Mosdepth \nuses a simple algorithm that is computationally efficient and enables it to \nquickly produce coverage summaries. We demonstrate that mosdepth is faster than \nexisting tools and provides flexibility in the types of coverage profiles \nproduced.\nAVAILABILITY AND IMPLEMENTATION: mosdepth is available from \nhttps://github.com/brentp/mosdepth under the MIT license.\nCONTACT: bpederse@gmail.com.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline."
] | nan |
60579cb394d57fd87900002e | [
31684860
] | train | Which tool has been developed for microRNA-target enrichment and network-based analysis? | factoid | MIENTURNET (MicroRNA ENrichment TURned NETwork) is a web tool that receives in input a list of miRNAs or mRNAs and tackles the problem of prioritizing miRNA-target interactions by performing a statistical analysis followed by a fully featured network-based visualization and analysis. The statistics is used to assess the significance of an over-representation of miRNA-target interactions and then MIENTURNET filters based on the statistical significance associated with each miRNA-target interaction. In addition, the holistic approach of the network theory is used to infer possible evidences of miRNA regulation by capturing emergent properties of the miRNA-target regulatory network that would be not evident through a pairwise analysis of the individual components. | MIENTURNET | [
"BACKGROUND: miRNAs regulate the expression of several genes with one miRNA able \nto target multiple genes and with one gene able to be simultaneously targeted by \nmore than one miRNA. Therefore, it has become indispensable to shorten the long \nlist of miRNA-target interactions to put in the spotlight in order to gain \ninsight into understanding the regulatory mechanism orchestrated by miRNAs in \nvarious cellular processes. A reasonable solution is certainly to prioritize \nmiRNA-target interactions to maximize the effectiveness of the downstream \nanalysis.\nRESULTS: We propose a new and easy-to-use web tool MIENTURNET (MicroRNA \nENrichment TURned NETwork) that receives in input a list of miRNAs or mRNAs and \ntackles the problem of prioritizing miRNA-target interactions by performing a \nstatistical analysis followed by a fully featured network-based visualization \nand analysis. The statistics is used to assess the significance of an \nover-representation of miRNA-target interactions and then MIENTURNET filters \nbased on the statistical significance associated with each miRNA-target \ninteraction. In addition, the holistic approach of the network theory is used to \ninfer possible evidences of miRNA regulation by capturing emergent properties of \nthe miRNA-target regulatory network that would be not evident through a pairwise \nanalysis of the individual components.\nCONCLUSION: MIENTURNET offers the possibility to consistently perform both \nstatistical and network-based analyses by using only a single tool leading to a \nmore effective prioritization of the miRNA-target interactions. This has the \npotential to avoid researchers without computational and informatics skills to \nnavigate multiple websites and thus to independently investigate miRNA activity \nin every cellular process of interest in an easy and at the same time exhaustive \nway thanks to the intuitive web interface. The web application along with a \nwell-documented and comprehensive user guide are freely available at \nhttp://userver.bio.uniroma1.it/apps/mienturnet/ without any login requirement."
] | nan |
5e52a7b66d0a277941000045 | [
28395661
] | train | Which tool has been developed for prediction of single-cell DNA methylation states using deep learning? | factoid | DeepCpG is a computational approach based on deep neural networks to predict methylation states in single cells. By evaluating DeepCpG on single-cell methylation data from five cell types generated using alternative sequencing protocols it turns out that DeepCpG yields substantially more accurate predictions than previous methods. | DeepCpG | [
"Recent technological advances have enabled DNA methylation to be assayed at \nsingle-cell resolution. However, current protocols are limited by incomplete CpG \ncoverage and hence methods to predict missing methylation states are critical to \nenable genome-wide analyses. We report DeepCpG, a computational approach based \non deep neural networks to predict methylation states in single cells. We \nevaluate DeepCpG on single-cell methylation data from five cell types generated \nusing alternative sequencing protocols. DeepCpG yields substantially more \naccurate predictions than previous methods. Additionally, we show that the model \nparameters can be interpreted, thereby providing insights into how sequence \ncomposition affects methylation variability."
] | nan |
62005e02c9dfcb9c09000018 | [
27048983
] | train | Which tool has been developed for proteome-wide detection of membrane lipid-binding proteins? | factoid | MBPpred is a profile Hidden Markov Model based method capable of detecting Membrane Binding Proteins (MBPs) from information encoded in their amino acid sequence. | MBPpred | [
"A large number of modular domains that exhibit specific lipid binding properties \nare present in many membrane proteins involved in trafficking and signal \ntransduction. These domains are present in either eukaryotic peripheral membrane \nor transmembrane proteins and are responsible for the non-covalent interactions \nof these proteins with membrane lipids. Here we report a profile Hidden Markov \nModel based method capable of detecting Membrane Binding Proteins (MBPs) from \ninformation encoded in their amino acid sequence, called MBPpred. The method \nidentifies MBPs that contain one or more of the Membrane Binding Domains (MBDs) \nthat have been described to date, and further classifies these proteins based on \ntheir position in respect to the membrane, either as peripheral or \ntransmembrane. MBPpred is available online at \nhttp://bioinformatics.biol.uoa.gr/MBPpred. This method was applied in selected \neukaryotic proteomes, in order to examine the characteristics they exhibit in \nvarious eukaryotic kingdoms and phyla."
] | nan |
5c56b96e07647bbc4b000010 | [
29788413
] | train | Which tool has been developed for tagging biomedical concepts via interactive learning? | factoid | ezTag is a web-based annotation tool that supports annotating a wide variety of biological concepts with or without pre-existing training data. It allows curators to perform annotation and provide training data with humans in the loop. ezTag supports both abstracts in PubMed and full-text articles in PubMed Central. It also provides lexicon-based concept tagging as well as the state-of-the-art pre-trained taggers such as TaggerOne, GNormPlus and tmVar. ezTag is freely available at http://eztag.bioqrator.org. | ezTag | [
"Recently, advanced text-mining techniques have been shown to speed up manual \ndata curation by providing human annotators with automated pre-annotations \ngenerated by rules or machine learning models. Due to the limited training data \navailable, however, current annotation systems primarily focus only on common \nconcept types such as genes or diseases. To support annotating a wide variety of \nbiological concepts with or without pre-existing training data, we developed \nezTag, a web-based annotation tool that allows curators to perform annotation \nand provide training data with humans in the loop. ezTag supports both abstracts \nin PubMed and full-text articles in PubMed Central. It also provides \nlexicon-based concept tagging as well as the state-of-the-art pre-trained \ntaggers such as TaggerOne, GNormPlus and tmVar. ezTag is freely available at \nhttp://eztag.bioqrator.org."
] | nan |
5c6d65637c78d69471000038 | [
29335563
] | train | Which tool has been developed for visualization of non-covalent contacts? | factoid | Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. The Protein Contacts Atlas has been developed as an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. This resource enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein-ligand contacts and by mapping external information. | Protein Contacts Atlas | [
"Visualizations of biomolecular structures empower us to gain insights into \nbiological functions, generate testable hypotheses, and communicate biological \nconcepts. Typical visualizations (such as ball and stick) primarily depict \ncovalent bonds. In contrast, non-covalent contacts between atoms, which govern \nnormal physiology, pathogenesis, and drug action, are seldom visualized. We \npresent the Protein Contacts Atlas, an interactive resource of non-covalent \ncontacts from over 100,000 PDB crystal structures. We developed multiple \nrepresentations for visualization and analysis of non-covalent contacts at \ndifferent scales of organization: atoms, residues, secondary structure, \nsubunits, and entire complexes. The Protein Contacts Atlas enables researchers \nfrom different disciplines to investigate diverse questions in the framework of \nnon-covalent contacts, including the interpretation of allostery, disease \nmutations and polymorphisms, by exploring individual subunits, interfaces, and \nprotein-ligand contacts and by mapping external information. The Protein \nContacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also \nthrough PDBe."
] | nan |
621911323a8413c653000038 | [
34864893
] | train | Which tool has been developed to discover VNTR-associated deletions? | factoid | Τrfermikit is a software tool designed to detect deletions larger than 50 bp occurring in Variable Number Tandem Repeats (VNTRs) using Illumina DNA sequencing reads. In such regions, it achieves a better trade-off between sensitivity and false discovery than a state-of-the-art structural variation (SV) caller, Manta, and complements it by recovering a significant number of deletions that Manta missed. trfermikit is based upon the fermikit pipeline, which performs read assembly, maps the assembly to the reference genome, and calls variants from the alignment. | trfermikit | [
"SUMMARY: We present trfermikit, a software tool designed to detect deletions \nlarger than 50 bp occurring in Variable Number Tandem Repeats using Illumina DNA \nsequencing reads. In such regions, it achieves a better tradeoff between \nsensitivity and false discovery than a state-of-the-art structural variation \ncaller, Manta and complements it by recovering a significant number of deletions \nthat Manta missed. trfermikit is based upon the fermikit pipeline, which \nperforms read assembly, maps the assembly to the reference genome and calls \nvariants from the alignment.\nAVAILABILITY AND IMPLEMENTATION: https://github.com/petermchale/trfermikit.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline."
] | nan |
621e59ce3a8413c65300004c | [
34864901
] | train | Which tool has been developed to identify the glycan shielding of glycosylated proteins? | factoid | GLYCO (GLYcan COverage) is an in silico approach to quantify the glycan shielding of a protein surface. The software provides insights into glycan-dense/sparse regions of the entire protein surface or a subset of the protein surface. GLYCO calculates glycan shielding from a single coordinate file or from multiple coordinate files, for instance, as obtained from molecular dynamics simulations or by nuclear magnetic resonance spectroscopy structure determination, enabling analysis of glycan dynamics. | GLYCO | [
"MOTIVATION: Glycans play important roles in protein folding and cell-cell \ninteractions-and, furthermore, glycosylation of protein antigens can \ndramatically impact immune responses. While there have been attempts to quantify \nthe glycan shielding or coverage of a protein surface, none of the publicly \navailable tools analyzes glycan shielding computationally at an atomistic level.\nRESULTS: Here, we developed an in silico approach, GLYCO (GLYcan COverage), to \nquantify the glycan shielding of a protein surface. The software provides \ninsights into glycan-dense/sparse regions of the entire protein surface or a \nsubset of the protein surface. GLYCO calculates glycan shielding from a single \ncoordinate file or from multiple coordinate files, for instance, as obtained \nfrom molecular dynamics simulations or by nuclear magnetic resonance \nspectroscopy structure determination, enabling analysis of glycan dynamics. \nOverall, GLYCO provides fundamental insights into the glycan shielding of \nglycosylated proteins.\nAVAILABILITY AND IMPLEMENTATION: GLYCO is freely available at GitHub \n(https://github.com/myungjinlee/GLYCO).\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline."
] | nan |
587e0116ae05ffb474000002 | [
20007090
] | train | Which tool is available for predicting regulatory interactions from ChIP-seq data? | factoid | CisMapper predicts the regulatory targets of a TF using the correlation between a histone mark at the TF's bound sites and the expression of each gene across a panel of tissues. CisMapper is more accurate at predicting the target genes of a TF than the distance-based approaches currently used, and is particularly advantageous for predicting the long-range regulatory interactions typical of tissue-specific gene expression. CisMapper also predicts which TF binding sites regulate a given gene more accurately than using genomic distance. Unlike distance-based methods, CisMapper can predict which transcription start site of a gene is regulated by a particular binding site of the TF. | CisMapper | [
"1. "
] | nan |
56afe6d40a360a5e45000017 | [
25653163
] | train | Which tool is used for promoterome mining using CAGE data? | factoid | Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. CAGEr is an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. | CAGEr | [
"Cap analysis of gene expression (CAGE) is a high-throughput method for \ntranscriptome analysis that provides a single base-pair resolution map of \ntranscription start sites (TSS) and their relative usage. Despite their high \nresolution and functional significance, published CAGE data are still underused \nin promoter analysis due to the absence of tools that enable its efficient \nmanipulation and integration with other genome data types. Here we present \nCAGEr, an R implementation of novel methods for the analysis of differential TSS \nusage and promoter dynamics, integrated with CAGE data processing and \npromoterome mining into a first comprehensive CAGE toolbox on a common analysis \nplatform. Crucially, we provide collections of TSSs derived from most published \nCAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous \nhuman and mouse cell/tissue types from within R, greatly increasing the \naccessibility of precise context-specific TSS data for integrative analyses. The \nCAGEr package is freely available from Bioconductor at \nhttp://www.bioconductor.org/packages/release/bioc/html/CAGEr.html."
] | nan |
589635dd78275d0c4a000009 | [
26304545
] | train | Which tool is used for the identification of recurrent variants in noncoding regions? | factoid | LARVA is an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. | LARVA | [
"In cancer research, background models for mutation rates have been extensively \ncalibrated in coding regions, leading to the identification of many driver \ngenes, recurrently mutated more than expected. Noncoding regions are also \nassociated with disease; however, background models for them have not been \ninvestigated in as much detail. This is partially due to limited noncoding \nfunctional annotation. Also, great mutation heterogeneity and potential \ncorrelations between neighboring sites give rise to substantial overdispersion \nin mutation count, resulting in problematic background rate estimation. Here, we \naddress these issues with a new computational framework called LARVA. It \nintegrates variants with a comprehensive set of noncoding functional elements, \nmodeling the mutation counts of the elements with a β-binomial distribution to \nhandle overdispersion. LARVA, moreover, uses regional genomic features such as \nreplication timing to better estimate local mutation rates and mutational \nhotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor \nsequences, showing that it identifies well-known noncoding drivers, such as \nmutations in the TERT promoter. Furthermore, LARVA highlights several novel \nhighly mutated regulatory sites that could potentially be noncoding drivers. We \nmake LARVA available as a software tool and release our highly mutated \nannotations as an online resource (larva.gersteinlab.org)."
] | ['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000071184', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012045'] |
5c6acb107c78d6947100001f | [
29659705
] | train | Which tool is used to visualise the junction sites of chloroplast genomes? | factoid | IRscope is an online program to visualize the junction sites of chloroplast genomes. It allows the users to depict the genetic architecture of up to ten chloroplast genomes in the vicinity of the sites connecting the inverted repeats to the short and long single copy regions. The software and its dependent libraries are fully coded in R and the reflected plot is scaled up to realistic size of nucleotide base pairs in the vicinity of the junction sites. The input of the program is an annotation GenBank (.gb) file, the accession or GI number of the sequence or a DOGMA output file. | IRscope | [
"MOTIVATION: Genome plotting is performed using a wide range of visualizations \ntools each with emphasis on a different informative dimension of the genome. \nThese tools can provide a deeper insight into the genomic structure of the \norganism.\nRESULTS: Here, we announce a new visualization tool that is specifically \ndesigned for chloroplast genomes. It allows the users to depict the genetic \narchitecture of up to ten chloroplast genomes in the vicinity of the sites \nconnecting the inverted repeats to the short and long single copy regions. The \nsoftware and its dependent libraries are fully coded in R and the reflected plot \nis scaled up to realistic size of nucleotide base pairs in the vicinity of the \njunction sites. We introduce a website for easier use of the program and R \nsource code of the software to be used in case of preferences to be changed and \nintegrated into personal pipelines. The input of the program is an annotation \nGenBank (.gb) file, the accession or GI number of the sequence or a DOGMA output \nfile. The software was tested using over a 100 embryophyte chloroplast genomes \nand in all cases a reliable output was obtained.\nAVAILABILITY AND IMPLEMENTATION: Source codes and the online suit available at \nhttps://irscope.shinyapps.io/irapp/ or https://github.com/Limpfrog/irscope."
] | nan |
5c6c497d7c78d69471000036 | [
29186450,
17119010,
24436254
] | train | Which tools have been developed for computing split-networks? | list | Split-networks are a generalization of phylogenetic trees that have proven to be a powerful tool in phylogenetics. Tools for computing such networks include SPECTRE, FlatNJ and QNet. | ['SPECTRE', 'FlatNJ', 'QNet'] | [
"SUMMARY: Split-networks are a generalization of phylogenetic trees that have \nproven to be a powerful tool in phylogenetics. Various ways have been developed \nfor computing such networks, including split-decomposition, NeighborNet, QNet \nand FlatNJ. Some of these approaches are implemented in the user-friendly \nSplitsTree software package. However, to give the user the option to adjust and \nextend these approaches and to facilitate their integration into analysis \npipelines, there is a need for robust, open-source implementations of associated \ndata structures and algorithms. Here, we present SPECTRE, a readily available, \nopen-source library of data structures written in Java, that comes complete with \nnew implementations of several pre-published algorithms and a basic interactive \ngraphical interface for visualizing planar split networks. SPECTRE also supports \nthe use of longer running algorithms by providing command line interfaces, which \ncan be executed on servers or in High Performance Computing environments.\nAVAILABILITY AND IMPLEMENTATION: Full source code is available under the GPLv3 \nlicense at: https://github.com/maplesond/SPECTRE. SPECTRE's core library is \navailable from Maven Central at: \nhttps://mvnrepository.com/artifact/uk.ac.uea.cmp.spectre/core. Documentation is \navailable at: \nhttp://spectre-suite-of-phylogenetic-tools-for-reticulate-evolution.readthedocs.io/en/latest/.\nCONTACT: sarah.bastkowski@earlham.ac.uk.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline.",
"We present QNet, a method for constructing split networks from weighted quartet \ntrees. QNet can be viewed as a quartet analogue of the distance-based \nNeighbor-Net (NNet) method for network construction. Just as NNet, QNet works by \nagglomeratively computing a collection of circular weighted splits of the taxa \nset which is subsequently represented by a planar split network. To illustrate \nthe applicability of QNet, we apply it to a previously published Salmonella data \nset. We conclude that QNet can provide a useful alternative to NNet if distance \ndata are not available or a character-based approach is preferred. Moreover, it \ncan be used as an aid for determining when a quartet-based tree-building method \nmay or may not be appropriate for a given data set. QNet is freely available for \ndownload.",
"Split networks are a type of phylogenetic network that allow visualization of \nconflict in evolutionary data. We present a new method for constructing such \nnetworks called FlatNetJoining (FlatNJ). A key feature of FlatNJ is that it \nproduces networks that can be drawn in the plane in which labels may appear \ninside of the network. For complex data sets that involve, for example, \nnon-neutral molecular markers, this can allow additional detail to be visualized \nas compared to previous methods such as split decomposition and NeighborNet. We \nillustrate the application of FlatNJ by applying it to whole HIV genome \nsequences, where recombination has taken place, fluorescent proteins in corals, \nwhere ancestral sequences are present, and mitochondrial DNA sequences from gall \nwasps, where biogeographical relationships are of interest. We find that the \nnetworks generated by FlatNJ can facilitate the study of genetic variation in \nthe underlying molecular sequence data and, in particular, may help to \ninvestigate processes such as intra-locus recombination. FlatNJ has been \nimplemented in Java and is freely available at \nwww.uea.ac.uk/computing/software/flatnj."
] | nan |
602918381cb411341a00010c | [
33005306,
31680159
] | train | Which tools have been developed for identifying and visualising ncRNA promoters? | list | Epd, ncpro-ml and ucsc genome browser are tools that have been developed for identifying and visualising ncRNA promoters. | ['Eukaryotic Promoter Database', 'ncPro-ML'] | [
"The promoter is located near the transcription start sites and regulates \ntranscription initiation of the gene. Accurate identification of promoters is \nessential for understanding the mechanism of gene regulation. Since experimental \nmethods are costly and ineffective, developing efficient and accurate \ncomputational tools to identify promoters are necessary. Although a series of \nmethods have been proposed for identifying promoters, none of them is able to \nidentify the promoters of non-coding RNA (ncRNA). In the present work, a new \nmethod called ncPro-ML was proposed to identify the promoter of ncRNA in Homo \nsapiens and Mus musculus, in which different kinds of sequence encoding schemes \nwere used to convert DNA sequences into feature vectors. To test the length \neffect, for each species, datasets including sequences with different lengths \nwere built. The results demonstrated that ncPro-ML achieved the best performance \nbased on the dataset with the sequence length of 221 nucleotides for human and \nmouse. The performances of ncPro-ML were also satisfying from both independent \ndataset test and cross-species test. The results indicate that the proposed \npredictor can server as a powerful tool for the discovery of ncRNA promoters. In \naddition, a web-server for ncPro-ML was developed, which can be freely accessed \nat http://www.bio-bigdata.cn/ncPro-ML/.",
"The Eukaryotic Promoter Database (EPD), available online at https://epd.epfl.ch, \nprovides accurate transcription start site (TSS) information for promoters of 15 \nmodel organisms plus corresponding functional genomics data that can be viewed \nin a genome browser, queried or analyzed via web interfaces, or exported in \nstandard formats (FASTA, BED, CSV) for subsequent analysis with other tools. \nRecent work has focused on the improvement of the EPD promoter viewers, which \nuse the UCSC Genome Browser as visualization platform. Thousands of \nhigh-resolution tracks for CAGE, ChIP-seq and similar data have been generated \nand organized into public track hubs. Customized, reproducible promoter views, \ncombining EPD-supplied tracks with native UCSC Genome Browser tracks, can be \naccessed from the organism summary pages or from individual promoter entries. \nMoreover, thanks to recent improvements and stabilization of ncRNA gene \ncatalogs, we were able to release promoter collections for certain classes of \nncRNAs from human and mouse. Furthermore, we developed automatic computational \nprotocols to assign orphan TSS peaks to downstream genes based on paired-end \n(RAMPAGE) TSS mapping data, which enabled us to add nearly 9000 new entries to \nthe human promoter collection. Since our last article in this journal, EPD was \nextended to five more model organisms: rhesus monkey, rat, dog, chicken and \nPlasmodium falciparum."
] | nan |
5a4e50b242878bf97d000001 | [
18570880,
21767457,
16651657,
2842762,
6090122,
6323017,
2840207,
23935120,
12888496,
1316274,
7932731,
1332607
] | train | Which topoisomerase is essential in yeast? | factoid | Eukaryotic DNA topoisomerase II is an abundant nuclear enzyme that is essential for cell proliferation. Yeast DNA topoisomerase II is encoded by a single-copy, essential gene. | topoisomerase II or topo II | [
"Type II topoisomerases are essential for resolving topologically entwined \ndouble-stranded DNA. Although anti-topoisomerase 2 (Top2) drugs are clinically \nimportant antibiotics and chemotherapies, to our knowledge, the mechanisms of \ncell killing by Top2 depletion and inactivation have never been directly \ncompared. We show that depletion of Top2 protein from budding yeast cells \nprevents DNA decatenation during S phase. Cells complete DNA replication and \nenter the ensuing mitosis on schedule, suffering extensive chromosome \nmissegregation. Cytokinesis through incompletely segregated chromosomes causes \nlethal DNA damage. By contrast, expression of catalytically inactive Top2 causes \na stable G2 arrest requiring an intact DNA damage checkpoint. Checkpoint \nactivation correlates with an inability to complete DNA replication, resulting \nin hypercatenated, gapped daughter DNA molecules. Thus, Top2 depletion and \ninactivation kill cells by different mechanisms, which has implications for \nunderstanding the nature of the catenation checkpoint, how DNA replication \nterminates, how anti-Top2 drugs work, and how new drugs might be designed.",
"DNA topoisomerases are specialized nuclear enzymes that perform topological \nmodifications on double-stranded DNA (dsDNA) and hence are essential for DNA \nmetabolism such as replication, transcription, recombination, condensation and \nsegregation. In a genetic screen, we identified a temperature-sensitive mutant \nallele of topoisomerase 2 that exhibits conditional synthetic lethality with a \nchk1 knockout strain. The mutant allele of topoisomerase 2 is defective in \nchromosome segregation at a non-permissive temperature and there was increase in \nchromosome segregation defects in the double mutant of top2-10 and chk1 delete \nat a non-permissive temperature. More importantly, topoisomearse 2 mutant cells \nmildly delay the mitotic progression at non-permissive temperature that is \nmediated by checkpoint protein kinase Chk1. Additionally, top2-10 mutant cells \nalso activate the Chk1 at a non-permissive temperature and this activation of \nChk1 takes place at the time of mitosis. Interestingly, top2-10 mutant cells \nretain their viability at a non-permissive temperature if the cells are not \nallowed to enter into mitosis. Taking together our results, we speculate that in \nthe top2-10 mutant, the segregation of entangled chromatids during mitosis could \nresult in delaying the mitotic progression through the activation of Chk1 \nkinase.",
"Topoisomerase II (Topo II) performs topological modifications on double-stranded \nDNA molecules that are essential for chromosome condensation, resolution, and \nsegregation. In mammals, G2 and metaphase cell cycle delays induced by Topo II \npoisons have been proposed to be the result of checkpoint activation in response \nto the catenation state of DNA. However, the apparent lack of such controls in \nmodel organisms has excluded genetic proof that Topo II checkpoints exist and \nare separable from the conventional DNA damage checkpoint controls. But here, we \ndefine a Topo II-dependent G2/M checkpoint in a genetically amenable eukaryote, \nbudding yeast, and demonstrate that this checkpoint enhances cell survival. \nConversely, a lack of the checkpoint results in aneuploidy. Neither DNA \ndamage-responsive pathways nor Pds1/securin are needed for this checkpoint. \nUnusually, spindle assembly checkpoint components are required for the Topo II \ncheckpoint, but checkpoint activation is not the result of failed chromosome \nbiorientation or a lack of spindle tension. Thus, compromised Topo II function \nactivates a yeast checkpoint system that operates by a novel mechanism.",
"Since DNA topoisomerase II (EC 5.99.1.3) is an essential enzyme in yeast, \nheterologous topoisomerase II gene expression in yeast cells can provide a \nsystem for analyzing the structure and function of topoisomerase II genes from \nother species. A series of yeast expression plasmids was constructed in which \nsegments of the cDNA sequences encoding Drosophila DNA topoisomerase II were \ninserted under the transcriptional control of yeast GAL1 promoter. Expression of \nthe functional form of Drosophila topoisomerase II cDNA can complement \nconditionally lethal, temperature-sensitive mutations in the yeast topoisomerase \nII gene (TOP2), as well as mutations in which the TOP2 locus was disrupted. The \nsurvival of these yeast cells depends upon the continuous expression of \nDrosophila topoisomerase II. Repression of Drosophila gene expression by glucose \ncauses these yeast cells to cease dividing after a few generations. In addition \nto these genetic complementation data, the expression of the Drosophila \ntopoisomerase II gene in yeast cells with a disruption in TOP2 can also be \ndetected by immunochemical methods with an antibody specific for Drosophila \ntopoisomerase II.",
"We have isolated mutants defective in DNA topoisomerases and an endonuclease \nfrom the fission yeast Schizosaccharomyces pombe by screening individual \nextracts of mutagenized cells. Two type I topoisomerase mutants (top1) and three \nendonuclease mutants (end1) were all viable. The double mutant top1 end1 was \nalso viable and, in its extract, Mg2+- and ATP- dependent type II activity could \nbe detected. Three temperature-sensitive (ts-) mutants having heat-sensitive \n(hs-) type II enzymes were isolated, and the ts- marker cosegregated with the \nhs- type II activity. All the ts- mutations fell in one gene (top2) tightly \nlinked to leul in chromosome II. The nuclear division of single top2 mutants was \nblocked at the restrictive temperature, but the formation of a septum was not \ninhibited so that the nucleus was cut across with the cell plate. In contrast, \nthe double top1 top2 mutants were rapidly arrested at various stages of the cell \ncycle, showing a strikingly altered nuclear chromatin region. The type II \ntopoisomerase may have an essential role in the compaction and/or segregation of \nchromosomes during the nuclear division but also complement the defect of the \ntype I enzyme whose major function is the maintenance of chromatin organization \nthroughout the cell cycle.",
"The gene TOP2 encoding yeast topoisomerase II has been cloned by immunological \nscreening of a yeast genomic library constructed in the phage lambda expression \nvector, lambda gt11. The ends of the message encoded by the cloned DNA fragment \nwere delimited by the Berk and Sharp procedure (S1 nuclease mapping) for the 5' \nend and mapping of the polyA tail portion of a cDNA fragment for the 3' end. The \npredicted size of the message agrees with the length of the message as \ndetermined by Northern blot hybridization analysis. The identity of the gene was \nconfirmed by expressing the gene in E. coli from the E. coli promoter lac UV5 to \ngive catalytically active yeast DNA topoisomerase II. Disruption of one copy of \nthe gene in a diploid yeast creates a recessive lethal mutation, indicating that \nthe single DNA topoisomerase II gene of yeast has an essential function.",
"Studies with yeast DNA topoisomerase mutants indicate that neither topoisomerase \nI nor II appears to be essential for transcription by RNA polymerase II. \nHowever, plasmids carrying transcriptionally active genes are found to be \nextremely negatively supercoiled when isolated from mutants lacking \ntopoisomerase I. Supercoiling occurs during transcriptional elongation rather \nthan during transcriptional activation. It takes place in the absence of \ntopoisomerase I and does not seem to be dependent on topoisomerase II since it \ncan occur at the nonpermissive temperature in a top1-top2 ts mutant. Whether \nthis change in linking number is due to an unusual form of topoisomerase II or \nwhether it is due to a new enzyme has yet to be determined. The results suggest \nthat topoisomerase I is normally required to relax transcriptionally induced \nsupercoils. A model is discussed which considers the role of topoisomerases in \nthe movement of RNA polymerase along the DNA template.",
"Eukaryotic topoisomerase II (topo II) is the essential decatenase of newly \nreplicated chromosomes and the main relaxase of nucleosomal DNA. Apart from \nthese general tasks, topo II participates in more specialized functions. In \nmammals, topo IIα interacts with specific RNA polymerases and \nchromatin-remodeling complexes, whereas topo IIβ regulates developmental genes \nin conjunction with chromatin remodeling and heterochromatin transitions. Here \nwe show that in budding yeast, topo II regulates the expression of specific gene \nsubsets. To uncover this, we carried out a genomic transcription run-on shortly \nafter the thermal inactivation of topo II. We identified a modest number of \ngenes not involved in the general stress response but strictly dependent on topo \nII. These genes present distinctive functional and structural traits in \ncomparison with the genome average. Yeast topo II is a positive regulator of \ngenes with well-defined promoter architecture that associates to chromatin \nremodeling complexes; it is a negative regulator of genes extremely \nhypo-acetylated with complex promoters and undefined nucleosome positioning, \nmany of which are involved in polyamine transport. These findings indicate that \nyeast topo II operates on singular chromatin architectures to activate or \nrepress DNA transcription and that this activity produces functional responses \nto ensure chromatin stability.",
"Topoisomerase II is a ubiquitous enzyme that removes knots and tangles from the \ngenetic material by generating transient double-strand DNA breaks. While the \nenzyme cannot perform its essential cellular functions without cleaving DNA, \nthis scission activity is inherently dangerous to chromosomal integrity. In \nfact, etoposide and other clinically important anticancer drugs kill cells by \nincreasing levels of topoisomerase II-mediated DNA breaks. Cells rely heavily on \nrecombination to repair double-strand DNA breaks, but the specific pathways used \nto repair topoisomerase II-generated DNA damage have not been defined. \nTherefore, Saccharomyces cerevisiae was used as a model system to delineate the \nrecombination pathways that repair DNA breaks generated by topoisomerase II. \nYeast cells that expressed wild-type or a drug-hypersensitive mutant \ntopoisomerase II or overexpressed the wild-type enzyme were examined. Based on \ncytotoxicity and recombination induced by etoposide in different \nrepair-deficient genetic backgrounds, double-strand DNA breaks generated by \ntopoisomerase II appear to be repaired primarily by the single-strand invasion \npathway of homologous recombination. Non-homologous end joining also was \ntriggered by etoposide treatment, but this pathway was considerably less active \nthan single-strand invasion and did not contribute significantly to cell \nsurvival in S.cerevisiae.",
"The decatenation activity of DNA topoisomerase II is essential for viability as \neukaryotic cells traverse mitosis. Phosphorylation has been shown to stimulate \ntopoisomerase II activity in vitro. Here we show that topoisomerase II is a \nphosphoprotein in yeast and that the level of incorporated phosphate is \nsignificantly higher at mitosis than in G1. Comparison of tryptic phosphopeptide \nmaps reveals that the major phosphorylation sites in vivo are targets for casein \nkinase II. Incorporation of phosphate into topoisomerase II is nearly \nundetectable at the non-permissive temperature in a conditional casein kinase II \nmutant. The sites modified by casein kinase II are located in the extreme \nC-terminal domain of topoisomerase II. This domain is absent in prokaryotic and \nhighly divergent among eukaryotic type II topoisomerases, and may serve to \nregulate functions of topoisomerase II that are unique to eukaryotic cells.",
"Eukaryotic DNA topoisomerase II is an abundant nuclear enzyme that is essential \nfor cell proliferation. This homodimeric enzyme catalyzes the cleavage and \nre-ligation of double-stranded DNA required to separate replicated sister \nchromatids. Both biochemical and genetic studies show that its catalytic \nactivity is required for chromosome condensation and segregation, and that its \ndecatenation activity can be stimulated by a variety of protein kinases in \nvitro. In budding yeast, topoisomerase II is most highly phosphorylated in \nmetaphase, and casein kinase II (CKII) was shown to be the major kinase \nmodifying topoisomerase II. We have investigated the effects of phosphorylation \nof yeast topoisomerase II by CKII in vitro, by means of gel-retardation and \nfilter binding assays. The phosphorylation of the C terminus of topoisomerase II \nby CKII appears to increase the stability of the complex formed with linear DNA \nfragments, while dephosphorylation has the opposite effect. Rephosphorylation of \nphosphatase-treated topoisomerase II by chicken casein kinase II restores a \nstable protein-DNA complex using a linear DNA fragment. The enhanced stability \nof the topoisomerase II-DNA complex is also observed with relaxed circular DNA, \nbut not with supercoiled minicircles, in agreement with published results using \ntopoisomerase II from Drosophila. Limited proteolysis and probing with \ndomain-specific antibodies shows that, with the exception of a weakly modified \nresidue between amino acid residues 660 and 1250, all residues modified by \ncasein kinase II are in the last 180 amino acid residues of yeast topoisomerase \nII.",
"The gene encoding topoisomerase II in yeast is unique and essential, required \nfor both mitotic and meiotic proliferation. The use of temperature-sensitive \nmutants in topoisomerase II have demonstrated roles in the relaxation of \ntortional stress, reduction of recombination rates, and in the separation of \nsister chromatids after replication. In vertebrate cells, topoisomerase II was \nshown to be the most abundant component of the metaphase chromosomal scaffold, \nand has been shown to play a role in chromosome condensation in vitro. The cell \ncycle control of chromosome condensation may well require phosphorylation of \ntopoisomerase II, since the enzyme is more highly phosphorylated in metaphase \nthan in G1. Recent studies have identified casein kinase II as the major enzyme \nphosphorylating topoisomerase II in intact yeast cells. The target sites of CKII \nare exclusively in the C-terminal 400 amino acids of topoisomerase II, the \nregion that is most divergent among the eukaryotic type II enzymes and which is \nabsent in the bacterial gyrase homologues."
] | nan |
56d138fe3975bb303a000015 | [
25436858,
19791510
] | train | Which trancription factor activates the betalain pathway? | factoid | The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway. | The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway. | [
"Nearly all flowering plants produce red/violet anthocyanin pigments. \nCaryophyllales is the only order containing families that replace anthocyanins \nwith unrelated red and yellow betalain pigments. Close biological correlation of \npigmentation patterns suggested that betalains might be regulated by a conserved \nanthocyanin-regulating transcription factor complex consisting of a MYB, a bHLH \nand a WD repeat-containing protein (the MBW complex). Here we show that a \npreviously uncharacterized anthocyanin MYB-like protein, Beta vulgaris MYB1 \n(BvMYB1), regulates the betalain pathway in beets. Silencing BvMYB1 \ndownregulates betalain biosynthetic genes and pigmentation, and overexpressing \nBvMYB1 upregulates them. However, unlike anthocyanin MYBs, BvMYB1 will not \ninteract with bHLH members of heterologous anthocyanin MBW complexes because of \nidentified nonconserved residues. BvMYB1 resides at the historic beet \npigment-patterning locus, Y, required for red-fleshed beets. We show that Y and \ny express different levels of BvMYB1 transcripts. The co-option of a \ntranscription factor regulating anthocyanin biosynthesis would be an important \nevolutionary event allowing betalains to largely functionally replace \nanthocyanins.",
"Betacyanins and anthocyanins, two main red flower pigments, never occur together \nin the same plant. Although the anthocyanin biosynthetic pathway has been well \nanalyzed, the biosynthetic genes and the regulatory mechanism of the betacyanin \nbiosynthesis are still obscure. We cloned two cDNAs of DOPA dioxygenase from \nPhytolacca americana, PaDOD1 and PaDOD2, that may be involved in the betalain \nbiosynthesis. The deduced amino acid sequence of PaDOD1 and PaDOD2 showed \napproximately 80% homology to each other. The promoter regions of PaDOD1 and \nPaDOD2 were isolated by inverse PCR and analyzed using PLACE database. Some \nputative MYB, bHLH, and environmental stress-responsive transcription factor \nbinding sites were detected in the PaDOD1 and PaDOD2 promoter regions. \nExpression patterns of PaDOD1 and PaDOD2 in suspension cultures of P. americana \nwere investigated by semiquantitative RT-PCR. The transcripts of PaDODs were \nfound in both betacyanin-producing red cells and non-betacyanin-producing white \ncells, suggesting that not only the expression of DOD, but also the \nsupplementation of DOPA might be a regulatory step for the betalain biosynthesis \nin P. americana."
] | nan |
5c74111f7c78d694710000a1 | [
23771139,
21896491
] | train | Which transcription factor binding site is contained in Alu repeats? | factoid | A novel abundant NF-κB-binding site resides in specialized Alu-repetitive elements having the potential for long range transcription regulation, thus suggesting that in addition to its known role, NF-κB has a primate-specific function and a role in human evolution. | The NF-κB-binding site | [
"Using nuclear factor-κB (NF-κB) ChIP-Seq data, we present a framework for \niterative learning of regulatory networks. For every possible transcription \nfactor-binding site (TFBS)-putatively regulated gene pair, the relative distance \nand orientation are calculated to learn which TFBSs are most likely to regulate \na given gene. Weighted TFBS contributions to putative gene regulation are \nintegrated to derive an NF-κB gene network. A de novo motif enrichment analysis \nuncovers secondary TFBSs (AP1, SP1) at characteristic distances from NF-κB/RelA \nTFBSs. Comparison with experimental ENCODE ChIP-Seq data indicates that \nexperimental TFBSs highly correlate with predicted sites. We observe that \nRelA-SP1-enriched promoters have distinct expression profiles from that of \nRelA-AP1 and are enriched in introns, CpG islands and DNase accessible sites. \nSixteen novel NF-κB/RelA-regulated genes and TFBSs were experimentally \nvalidated, including TANK, a negative feedback gene whose expression is \nNF-κB/RelA dependent and requires a functional interaction with the AP1 TFBSs. \nOur probabilistic method yields more accurate NF-κB/RelA-regulated networks than \na traditional, distance-based approach, confirmed by both analysis of gene \nexpression and increased informativity of Genome Ontology annotations. Our \nanalysis provides new insights into how co-occurring TFBSs and local chromatin \ncontext orchestrate activation of NF-κB/RelA sub-pathways differing in \nbiological function and temporal expression patterns.",
"The transcription factor NF-κB is a critical regulator of immune responses. To \ndetermine how NF-κB builds transcriptional control networks, we need to obtain a \ntopographic map of the factor bound to the genome and correlate it with global \ngene expression. We used a ChIP cloning technique and identified novel NF-κB \ntarget genes in response to virus infection. We discovered that most of the \nNF-κB-bound genomic sites deviate from the consensus and are located away from \nconventional promoter regions. Remarkably, we identified a novel abundant \nNF-κB-binding site residing in specialized Alu-repetitive elements having the \npotential for long range transcription regulation, thus suggesting that in \naddition to its known role, NF-κB has a primate-specific function and a role in \nhuman evolution. By combining these data with global gene expression profiling \nof virus-infected cells, we found that most of the sites bound by NF-κB in the \nhuman genome do not correlate with changes in gene expression of the nearby \ngenes and they do not appear to function in the context of synthetic promoters. \nThese results demonstrate that repetitive elements interspersed in the human \ngenome function as common target sites for transcription factors and may play an \nimportant role in expanding the repertoire of binding sites to engage new genes \ninto regulatory networks."
] | nan |
5e4bf9436d0a27794100002d | [
23300480,
23274689,
9819428,
28144959,
9570950,
17028039,
19050759,
9152013,
14648848,
33229432,
9291577,
17586813,
15893982,
25248479
] | train | Which transcription factor controls Drosophila's Hes genes? | factoid | The Notch/Hes axis represses a cohort of transcription factor genes . In Drosophila, activation of the Notch receptor induces transcriptional repressors encoded by the hairy/Enhancer of split (HES) genes, which shut off achaete-scute transcription . The molecular details of how Hes and Hey proteins control transcription are still poorly understood . | Notch | [
"Dynamic activity of signaling pathways, such as Notch, is vital to achieve \ncorrect development and homeostasis. However, most studies assess output many \nhours or days after initiation of signaling, once the outcome has been \nconsolidated. Here we analyze genome-wide changes in transcript levels, binding \nof the Notch pathway transcription factor, CSL [Suppressor of Hairless, Su(H), \nin Drosophila], and RNA Polymerase II (Pol II) immediately following a short \npulse of Notch stimulation. A total of 154 genes showed significant differential \nexpression (DE) over time, and their expression profiles stratified into 14 \nclusters based on the timing, magnitude, and direction of DE. E(spl) genes were \nthe most rapidly upregulated, with Su(H), Pol II, and transcript levels \nincreasing within 5-10 minutes. Other genes had a more delayed response, the \ntiming of which was largely unaffected by more prolonged Notch activation. \nNeither Su(H) binding nor poised Pol II could fully explain the differences \nbetween profiles. Instead, our data indicate that regulatory interactions, \ndriven by the early-responding E(spl)bHLH genes, are required. Proposed \ncross-regulatory relationships were validated in vivo and in cell culture, \nsupporting the view that feed-forward repression by E(spl)bHLH/Hes shapes the \nresponse of late-responding genes. Based on these data, we propose a model in \nwhich Hes genes are responsible for co-ordinating the Notch response of a wide \nspectrum of other targets, explaining the critical functions these key \nregulators play in many developmental and disease contexts.",
"The Notch pathway plays an important role in ovary development in invertebrates \nlike Drosophila. However its role for the mammalian ovary is unclear. Mammalian \nHes genes encode transcriptional factors that mediate many of the activities of \nthe Notch pathway. Here, we have studied the function of Hes1 during embryonic \ndevelopment of the mouse ovary. We find that Hes1 protein is present in somatic \ncells and oocyte cytoplasm and decreases between E15.5 and P0. Conventional Hes1 \nknock-out (KO), Hes1 conditional KO in the ovarian somatic, and chemical \ninhibition of Notch signaling decrease the total number, size and maturation of \noocytes and increase the number of pregranulosa cells at P0. These defects \ncorrelate with abnormal proliferation and enhanced apoptosis. Expression of the \nproapoptotic gene Inhbb is increased, while the levels of the antiapoptotic and \noocyte maturation marker Kit are decreased in the Hes1 KO ovaries. Conversely, \noveractivation of the Notch pathway in ovarian somatic cells increases the \nnumber of mature oocytes and decreases the number of pregranulosa cells. \nFertility is also reduced by either Hes1 deletion or Notch pathway \noveractivation. In conclusion, our data suggest that the Notch-Hes1 pathway \nregulates ovarian somatic cell development, which is necessary for oocyte \nsurvival and maturation.",
"The Notch receptor is involved in many cell fate determination events in \nvertebrates and invertebrates. It has been shown in Drosophila melanogaster that \nDelta-dependent Notch signaling activates the transcription factor Suppressor of \nHairless, leading to an increased expression of the Enhancer of Split genes. \nGenetic evidence has also implicated the kuzbanian gene, which encodes a \ndisintegrin metalloprotease, in the Notch signaling pathway. By using a two-cell \ncoculture assay, we show here that vertebrate Dl-1 activates the Notch-1 \ncascade. Consistent with previous data obtained with active forms of Notch-1 a \nHES-1-derived promoter construct is transactivated in cells expressing Notch-1 \nin response to Dl-1 stimulation. Impairing the proteolytic maturation of the \nfull-length receptor leads to a decrease in HES-1 transactivation, further \nsupporting the hypothesis that only mature processed Notch is expressed at the \ncell surface and activated by its ligand. Furthermore, we observed that \nDl-1-induced HES-1 transactivation was dependent both on Kuzbanian and RBP-J \nactivities, consistent with the involvement of these two proteins in Notch \nsignaling in Drosophila. We also observed that exposure of Notch-1-expressing \ncells to Dl-1 results in an increased level of endogenous HES-1 mRNA. Finally, \ncoculture of Dl-1-expressing cells with myogenic C2 cells suppresses \ndifferentiation of C2 cells into myotubes, as previously demonstrated for \nJagged-1 and Jagged-2, and also leads to an increased level of endogenous HES-1 \nmRNA. Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same \nability to suppress cell differentiation as the Jagged proteins do.",
"The Notch signaling pathway controls cell fate decision, proliferation, and \nother biological functions in both vertebrates and invertebrates. Precise \nregulation of the canonical Notch pathway ensures robustness of the signal \nthroughout development and adult tissue homeostasis. Aberrant Notch signaling \nresults in profound developmental defects and is linked to many human diseases. \nIn this study, we identified the Atrophin family protein RERE (also called \nAtro2) as a positive regulator of Notch target Hes genes in the developing \nvertebrate spinal cord. Prior studies have shown that during early embryogenesis \nin mouse and zebrafish, deficit of RERE causes various patterning defects in \nmultiple organs including the neural tube. Here, we detected the expression of \nRERE in the developing chick spinal cord, and found that normal RERE activity is \nneeded for proper neural progenitor proliferation and neuronal differentiation \npossibly by affecting Notch-mediated Hes expression. In mammalian cells, RERE \nco-immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is \nrecruited to nuclear foci formed by over-expressed NICD1. RERE is also necessary \nfor NICD to activate the expression of Notch target genes. Our findings suggest \nthat RERE stimulates Notch target gene expression by preventing degradation of \nNICD protein, thereby facilitating the assembly of a transcriptional activating \ncomplex containing NICD, CBF1/RBPjκ in vertebrate, Su(H) in Drosophila \nmelanogaster, Lag1 in C. elegans, and other coactivators.",
"Hes2 encodes a mammalian basic helix-loop-helix transcriptional repressor \nhomologous to the products of Drosophila hairy and Enhancer of split. Here, we \nisolated and characterized the mouse Hes2 gene. This gene consists of four \nexons, and all the introns are located within the protein-coding region at \npositions homologous to those of other Hes genes. On the inter-specific \nbackcross analyses, mouse Hes2 is mapped to the distal region of Chromosome 4 \nnear the Hes3 and Hes5 loci, which are different from the Hes1 locus on \nChromosome 16. Upstream of the transcription initiation site, there are GC-rich \nregions, but a typical TATA box is not present. Transient transfection analyses \ndemonstrated that, while Hes1 and Hes5 promoter activities are significantly \nupregulated by the active form of Notch, a key regulator of cellular \ndifferentiation, Hes2 and Hes3 promoter activities are not. These results \nsuggest that Hes genes are functionally classified into two groups: those that \nare regulated by Notch and those that are not.",
"HESR1 is a basic helix-loop-helix transcription factors regulated by the Notch \nsignaling pathway in vertebrate and Drosophila embryos, and is related to the \nHES/Hairy/E (sp1) family. HESR1 is a downstream target of Notch in endothelial \ncells and could be an effector of Notch signaling in these cells. HESR1 is \nnecessary for the induction of a tubular network and for continued maintenance \nof mature and quiescent blood vessels. To examine the role of HESR1 in retinal \nneovascularization, we transfected retinal vascular endothelial cells (HRCECs) \nwith the HESR1 gene and studied its effects on the expression of angiogenic \nfactors, on the proliferation and migration of endothelial cells, and on the \nformation of tube-like structures (TLSs). Overexpression of HESR1 downregulated \nVEGFR-2 expression, upregulated occludin expression, inhibited the migration and \nproliferation of HRCECs, and inhibited the formation of TLSs. Thus, HESR1 plays \na key role in the finely tuned network of molecules involved in the regulation \nof retinal vascular homeostasis. HESR1 seems to inhibit the vessel-promoting \neffects of VEGF, shift endothelial cells from a proliferative state to a \nquiescent state, and restore normal vessel structures. Expression of the HESR1 \ngene in retinal vascular endothelial cells may protect retinal blood vessels and \nmay be useful in the treatment of diseases involving damage to the retinal \nvasculature, including diabetic retinopathy, age-related macular degeneration, \nand retinal vein occlusion.",
"BACKGROUND: Establishment and maintenance of a functional central nervous system \n(CNS) requires a highly orchestrated process of neural progenitor cell \nproliferation, cell cycle exit, and differentiation. An evolutionary conserved \nprogram consisting of Notch signalling mediated by basic Helix-Loop-Helix (bHLH) \ntranscription factor activity is necessary for both the maintenance of neural \nprogenitor cell character and the progression of neurogenesis; however, \nadditional players in mammalian CNS neural specification remain largely unknown. \nIn Drosophila we recently characterized Hamlet, a transcription factor that \nmediates Notch signalling and neural cell fate.\nMETHODOLOGY/PRINCIPAL FINDINGS: Hamlet is a member of the Prdm (PRDI-BF1 and RIZ \nhomology domain containing) proto-oncogene transcription factor family, and in \nthis study we report that multiple genes in the Prdm family (Prdm6, 8, 12, 13 \nand 16) are expressed in the developing mouse CNS in a spatially and temporally \nrestricted manner. In developing spinal cord Prdm8, 12 and 13 are expressed in \nprecise neuronal progenitor zones suggesting that they may specify discrete \nneuronal subtypes. In developing telencephalon Prdm12 and 16 are expressed in \nthe ventricular zone in a lateral to medial graded manner, and Prdm8 is \nexpressed in a complementary domain in postmitotic neurons. In postnatal brain \nPrdm8 additionally shows restricted expression in cortical layers 2/3 and 4, the \nhippocampus, and the amygdala. To further elucidate roles of Prdm8 and 16 in the \ndeveloping telencephalon we analyzed the relationship between these factors and \nthe bHLH Hes (Hairy and enhancer of split homolog) effectors of Notch \nsignalling. In Hes null telencephalon neural differentiation is enhanced, Prdm8 \nexpression is upregulated, and Prdm16 expression is downregulated; conversely in \nutero electroporation of Hes1 into the developing telencephalon upregulates \nPrdm16 expression.\nCONCLUSIONS/SIGNIFICANCE: Our data demonstrate that Prdm genes are regulated by \nthe Notch-Hes pathway and represent strong candidates to control neural class \nspecification and the sequential progression of mammalian CNS neurogenesis.",
"The Hes gene family members are mammalian homologues of the Drosophila hairy and \nEnhancer of split genes. hairy and Enhancer of split function in both \nsegmentation and in the Notch neurogenic pathway during Drosophila embryo \ndevelopment. Previous expression data suggested a conserved role for the Hes \ngenes in the Notch signalling pathway, but not in segmentation. Here, Hes3 \nexpression during mouse embryogenesis is described. During early development of \nthe central nervous system, Hes3 is expressed specifically in the region of the \nmidbrain/hindbrain boundary, and in rhombomeres 2, 4, 6 and 7. This pattern \nsuggests that Hes3 may have a conserved role as a segmentation gene. Later in \ndevelopment, Hes3 is co-expressed with other neurogenic gene homologues in the \ndeveloping central nervous system and epithelial cells undergoing mesenchyme \ninduction.",
"Hairy-related transcription factor (HRT/Hey) genes encode a novel subfamily of \nbasic helix-loop-helix (bHLH) transcription factors related to the Drosophila \nhairy and Enhancer-of-split (E(spl)) and the mammalian HES proteins that \nfunction as downstream mediators of Notch signaling. Using the yeast two-hybrid \napproach, a previously uncharacterized protein was identified in Xenopus that \ninteracts with XHRT1 (originally referred to as bc8), one member of the HRT/Hey \nsubclass. This protein is evolutionarily conserved in chordates. It binds to \nsequences adjacent to the bHLH domain of XHRT1 known as the Orange domain and \nhas been named bc8 Orange interacting protein (BOIP). BOIP shows a rather \nuniform subcellular localization and is recruited to the nucleus upon binding to \nXHRT1. In Xenopus, XBOIP mRNA is detected by RNase protection analysis \nthroughout embryogenesis. In the adult, the strongest expression is detected in \ntestis. In the mouse, high levels of BOIP mRNA are also found in adult testis. \nNo expression is detected in the embryo and in any of the other adult organs \ntested. In situ hybridization revealed that BOIP transcripts were detected \nalmost exclusively in round spermatids and that this expression overlaps with \nthat of Hey1 (HRT1), which is expressed throughout spermatogenesis. In view of \nthe importance of the Orange domain for HRT/Hey function, the newly identified \nBOIP proteins may serve as regulators specifically of HRT1/Hey1 activity.",
"Neural stem cells divide during embryogenesis and juvenile life to generate the \nentire complement of neurons and glia in the nervous system of vertebrates and \ninvertebrates. Studies of the mechanisms controlling the fine balance between \nneural stem cells and more differentiated progenitors have shown that, in every \nasymmetric cell division, progenitors send a Delta-Notch signal to their sibling \nstem cells. Here, we show that excessive activation of Notch or overexpression \nof its direct targets of the Hes family causes stem-cell hyperplasias in the \nDrosophila larval central nervous system, which can progress to malignant \ntumours after allografting to adult hosts. We combined transcriptomic data from \nthese hyperplasias with chromatin occupancy data for Dpn, a Hes transcription \nfactor, to identify genes regulated by Hes factors in this process. We show that \nthe Notch/Hes axis represses a cohort of transcription factor genes. These are \nexcluded from the stem cells and promote early differentiation steps, most \nlikely by preventing the reversion of immature progenitors to a stem-cell fate. \nWe describe the impact of two of these 'anti-stemness' factors, Zfh1 and Gcm, on \nNotch/Hes-triggered tumorigenesis.",
"Mash-2 expression begins during preimplantation development, but is restricted \nto trophoblasts after the blastocyst stage. Within the trophoblast lineage, \nMash-2 transcripts are first expressed in the ectoplacental cone and chorion, \nbut not in terminally differentiated trophoblast giant cells. After day 8.5 of \ngestation, Mash-2 expression becomes further restricted to focal sites within \nthe spongiotrophoblast and labyrinth. Downregulation is probably important for \nnormal development since overexpression of Mash-2 reduces giant cell formation. \nWe have investigated the role that the Notch signaling pathway may play in \ntrophoblast development. Mash-2 is a homologue of Drosophila achaete/scute \ncomplex genes. In Drosophila, activation of the Notch receptor induces \ntranscriptional repressors encoded by the hairy/Enhancer of split (HES) genes, \nwhich interact with the Groucho protein to shut off achaete-scute transcription. \nIn the developing mouse placenta, we found that all elements of the Notch \npathway were expressed. In particular, the Notch-2, HES-2, and HES-3 genes were \ncoexpressed in trophoblast giant cells and in foci within the spongiotrophoblast \nat day 10.5 when Mash-2 transcription becomes restricted. Two members of the \nmammalian Groucho family were expressed in trophoblasts; TLE3 was expressed \nbroadly in the giant cell, spongiotrophoblast, and labyrinthine regions, whereas \nTLE2 was limited to giant cells and focal regions of the spongiotrophoblast. \nThese data suggest that Notch signaling through activation of HES \ntranscriptional repressors may play a role in murine placental development.",
"Hes and Hey genes are the mammalian counterparts of the Hairy and \nEnhancer-of-split type of genes in Drosophila and they represent the primary \ntargets of the Delta-Notch signaling pathway. Hairy-related factors control \nmultiple steps of embryonic development and misregulation is associated with \nvarious defects. Hes and Hey genes (also called Hesr, Chf, Hrt, Herp or \ngridlock) encode transcriptional regulators of the basic helix-loop-helix class \nthat mainly act as repressors. The molecular details of how Hes and Hey proteins \ncontrol transcription are still poorly understood, however. Proposed modes of \naction include direct binding to N- or E-box DNA sequences of target promoters \nas well as indirect binding through other sequence-specific transcription \nfactors or sequestration of transcriptional activators. Repression may rely on \nrecruitment of corepressors and induction of histone modifications, or even \ninterference with the general transcriptional machinery. All of these models \nrequire extensive protein-protein interactions. Here we review data published on \nprotein-protein and protein-DNA interactions of Hairy-related factors and \ndiscuss their implications for transcriptional regulation. In addition, we \nsummarize recent progress on the identification of potential target genes and \nthe analysis of mouse models.",
"HES transcriptional repressors are important components of the Notch pathway \nthat regulates neurogenesis from Drosophila to vertebrates. These proteins are \nnormally induced by Notch activity and inhibit neural commitment by antagonizing \nthe activity of proneural genes. We describe here four chick hes genes that are \nexpressed during neurogenesis: three hes5-like genes (hes5-1, hes5-2 and hes5-3) \nand one hes6-like (hes6-2). We show that hes6-2 represses transcription of the \nhes5 genes, thus functioning as a negative regulator of Notch signaling. \nConversely, hes6-2 may be repressed by hes5 activity. In cells committing to \ndifferentiation, we find that hes6-2 is up-regulated by proneural genes and \ncontributes to the proneural program of neuronal commitment by preventing Notch \nactivity in these cells. In neural progenitors, Notch signaling produces an \ninitial burst of hes5 activity, which represses hes6-2. However, as hes5 \ntranscription declines due to negative auto-regulation, hes6-2 may become active \nand inhibit the remaining hes5 activity to end Notch signaling. These cells can \nthen enter a new cycle of fate decisions and will be kept as progenitors if a \nnew pulse of Notch activity occurs. Maintenance of progenitors during vertebrate \nneurogenesis therefore requires that these cells go through successive cycles of \nNotch activity. We propose that the hes5/hes6 circuitry of negative \ncross-regulations is a conserved feature of the Notch pathway that underlies \nthese cycles in neural progenitors.",
"Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are \nmammalian homologues of Drosophila hairy and Enhancer of split genes, both of \nwhich are required for normal neurogenesis in Drosophila. There are seven \nmembers in the human Hes family, Hes1-7, which are expressed in many tissues and \nplay various roles mainly in development. All Hes proteins have three conserved \ndomains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to \ntarget DNA sequences, while the HLH region forms homo- and heterodimers with \nother bHLH proteins, the Orange domain is responsible for the selection of \npartners during heterodimer formation, and the WRPW domain recruits \ncorepressors. Hes1, Hes5, and Hes7 are known as downstream effectors of \ncanonical Notch signaling, which regulates cell differentiation via cell-cell \ninteraction. Hes factors regulate many events in development by repressing the \nexpression of target genes, many of which encode transcriptional activators that \npromote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly \nexpressed by neural stem cells, and inactivation of these genes results in \ninsufficient maintenance of stem cell proliferation and prematurely promotes \nneuronal differentiation. Recently, it was shown that the expression dynamics of \nHes1 plays crucial roles in proper developmental timings and fate-determination \nsteps of embryonic stem cells and neural progenitor cells. Here, we discuss some \nkey features of Hes factors in development and diseases."
] | nan |
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] | train | Which transcription factor is considered as a master regulator of lysosomal genes? | factoid | Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, driving lysosome adaptation to environmental cues, such as starvation, and therefore targeting of TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease. | Transcription factor EB (TFEB) | [
"The lysosomal-autophagic pathway is activated by starvation and plays an \nimportant role in both cellular clearance and lipid catabolism. However, the \ntranscriptional regulation of this pathway in response to metabolic cues is \nuncharacterized. Here we show that the transcription factor EB (TFEB), a master \nregulator of lysosomal biogenesis and autophagy, is induced by starvation \nthrough an autoregulatory feedback loop and exerts a global transcriptional \ncontrol on lipid catabolism via Ppargc1α and Ppar1α. Thus, during starvation a \ntranscriptional mechanism links the autophagic pathway to cellular energy \nmetabolism. The conservation of this mechanism in Caenorhabditis elegans \nsuggests a fundamental role for TFEB in the evolution of the adaptive response \nto food deprivation. Viral delivery of TFEB to the liver prevented weight gain \nand metabolic syndrome in both diet-induced and genetic mouse models of obesity, \nsuggesting a new therapeutic strategy for disorders of lipid metabolism.",
"Loss-of-function diseases are often caused by destabilizing mutations that lead \nto protein misfolding and degradation. Modulating the innate protein homeostasis \n(proteostasis) capacity may lead to rescue of native folding of the mutated \nvariants, thereby ameliorating the disease phenotype. In lysosomal storage \ndisorders (LSDs), a number of highly prevalent alleles have missense mutations \nthat do not impair the enzyme's catalytic activity but destabilize its native \nstructure, resulting in the degradation of the misfolded protein. Enhancing the \ncellular folding capacity enables rescuing the native, biologically functional \nstructure of these unstable mutated enzymes. However, proteostasis modulators \nspecific for the lysosomal system are currently unknown. Here, we investigate \nthe role of the transcription factor EB (TFEB), a master regulator of lysosomal \nbiogenesis and function, in modulating lysosomal proteostasis in LSDs. We show \nthat TFEB activation results in enhanced folding, trafficking and lysosomal \nactivity of a severely destabilized glucocerebrosidase (GC) variant associated \nwith the development of Gaucher disease (GD), the most common LSD. TFEB \nspecifically induces the expression of GC and of key genes involved in folding \nand lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and \nits processing through the secretory pathway. TFEB activation also rescues the \nactivity of a β-hexosaminidase mutant associated with the development of another \nLSD, Tay-Sachs disease, thus suggesting general applicability of TFEB-mediated \nproteostasis modulation to rescue destabilizing mutations in LSDs. In summary, \nour findings identify TFEB as a specific regulator of lysosomal proteostasis and \nsuggest that TFEB may be used as a therapeutic target to rescue enzyme \nhomeostasis in LSDs.",
"For a long time, lysosomes were considered merely to be cellular 'incinerators' \ninvolved in the degradation and recycling of cellular waste. However, now there \nis compelling evidence indicating that lysosomes have a much broader function \nand that they are involved in fundamental processes such as secretion, plasma \nmembrane repair, signalling and energy metabolism. Furthermore, the essential \nrole of lysosomes in autophagic pathways puts these organelles at the crossroads \nof several cellular processes, with significant implications for health and \ndisease. The identification of a master regulator, transcription factor EB \n(TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the \nlysosome adapts to environmental cues, such as starvation, and targeting TFEB \nmay provide a novel therapeutic strategy for modulating lysosomal function in \nhuman disease.",
"The lysosome plays a key role in cellular homeostasis by controlling both \ncellular clearance and energy production to respond to environmental cues. \nHowever, the mechanisms mediating lysosomal adaptation are largely unknown. \nHere, we show that the Transcription Factor EB (TFEB), a master regulator of \nlysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 \n(mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation \nof TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition \nof mTORC1, as well as starvation and lysosomal disruption, activates TFEB by \npromoting its nuclear translocation. In addition, the transcriptional response \nof lysosomal and autophagic genes to either lysosomal dysfunction or \npharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. \nInterestingly, the Rag GTPase complex, which senses lysosomal amino acids and \nactivates mTORC1, is both necessary and sufficient to regulate starvation- and \nstress-induced nuclear translocation of TFEB. These data indicate that the \nlysosome senses its content and regulates its own biogenesis by a \nlysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.",
"Cerium oxide nanoparticles (nanoceria) are widely used in a variety of \nindustrial applications including UV filters and catalysts. The expanding \ncommercial scale production and use of ceria nanoparticles have inevitably \nincreased the risk of release of nanoceria into the environment as well as the \nrisk of human exposure. The use of nanoceria in biomedical applications is also \nbeing currently investigated because of its recently characterized antioxidative \nproperties. In this study, we investigated the impact of ceria nanoparticles on \nthe lysosome-autophagy system, the main catabolic pathway that is activated in \nmammalian cells upon internalization of exogenous material. We tested a battery \nof ceria nanoparticles functionalized with different types of biocompatible \ncoatings (N-acetylglucosamine, polyethylene glycol and polyvinylpyrrolidone) \nexpected to have minimal effect on lysosomal integrity and function. We found \nthat ceria nanoparticles promote activation of the transcription factor EB, a \nmaster regulator of lysosomal function and autophagy, and induce upregulation of \ngenes of the lysosome-autophagy system. We further show that the array of \ndifferently functionalized ceria nanoparticles tested in this study enhance \nautophagic clearance of proteolipid aggregates that accumulate as a result of \ninefficient function of the lysosome-autophagy system. This study provides a \nmechanistic understanding of the interaction of ceria nanoparticles with the \nlysosome-autophagy system and demonstrates that ceria nanoparticles are \nactivators of autophagy and promote clearance of autophagic cargo. These results \nprovide insights for the use of nanoceria in biomedical applications, including \ndrug delivery. These findings will also inform the design of engineered \nnanoparticles with safe and precisely controlled impact on the environment and \nthe design of nanotherapeutics for the treatment of diseases with defective \nautophagic function and accumulation of lysosomal storage material.",
"When the levels of intracellular amino acids are high, RRAG GTPases recruit \nMTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit \nspecific MTORC1 substrates to the lysosomal surface, thus facilitating \nMTORC1-mediated phosphorylation and regulation. In particular, active RRAGs \ninteract with the transcription factor EB (TFEB), the master regulator of a gene \nnetwork that promotes lysosomal biogenesis and autophagy. Redistribution to \nlysosomes is critical for MTORC1-dependent inactivation of TFEB under \nnutrient-rich conditions. Therefore, RRAGs play a critical role coordinating \nnutrient availability and cellular clearance.",
"The mTORC1 complex supports cell growth and proliferation in response to energy \nlevels, growth factors, and nutrients. The Rag guanosine triphosphatases \n(GTPases) activate mTORC1 in response to amino acids by promoting its \nredistribution to lysosomes. In this paper, we identify a novel role for Rags in \ncontrolling activation of transcription factor EB (TFEB), a master regulator of \nautophagic and lysosomal gene expression. Interaction of TFEB with active Rag \nheterodimers promoted recruitment of TFEB to lysosomes, leading to \nmTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB \nwith Rags required the first 30 residues of TFEB and the switch regions of the \nRags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB \nto lysosomes, whereas expression of active Rags induced association of TFEB with \nlysosomal membranes. Finally, Rag GTPases bound and regulated activation of \nmicrophthalmia-associated transcription factor, suggesting a broader role for \nRags in the control of gene expression. Our work provides new insight into the \nmolecular mechanisms that link nutrient availability and TFEB localization and \nactivation.",
"Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that \nmediates adaptive responses to hypoxia. We demonstrate that lysosomal \ndegradation of the HIF-1α subunit by chaperone-mediated autophagy (CMA) is a \nmajor regulator of HIF-1 activity. Pharmacological inhibitors of lysosomal \ndegradation, such as bafilomycin and chloroquine, increased HIF-1α levels and \nHIF-1 activity, whereas activators of chaperone-mediated autophagy, including \n6-aminonicotinamide and nutrient starvation, decreased HIF-1α levels and HIF-1 \nactivity. In contrast, macroautophagy inhibitors did not increase HIF-1 \nactivity. Transcription factor EB, a master regulator of lysosomal biogenesis, \nalso negatively regulated HIF-1 activity. HIF-1α interacts with HSC70 and \nLAMP2A, which are core components of the CMA machinery. Overexpression of HSC70 \nor LAMP2A decreased HIF-1α protein levels, whereas knockdown had the opposite \neffect. Finally, hypoxia increased the transcription of genes involved in CMA \nand lysosomal biogenesis in cancer cells. Thus, pharmacological and genetic \napproaches identify CMA as a major regulator of HIF-1 activity and identify \ninterplay between autophagy and the response to hypoxia.",
"Autophagy is a cellular catabolic process that relies on the cooperation of \nautophagosomes and lysosomes. During starvation, the cell expands both \ncompartments to enhance degradation processes. We found that starvation \nactivates a transcriptional program that controls major steps of the autophagic \npathway, including autophagosome formation, autophagosome-lysosome fusion, and \nsubstrate degradation. The transcription factor EB (TFEB), a master gene for \nlysosomal biogenesis, coordinated this program by driving expression of \nautophagy and lysosomal genes. Nuclear localization and activity of TFEB were \nregulated by serine phosphorylation mediated by the extracellular \nsignal-regulated kinase 2, whose activity was tuned by the levels of \nextracellular nutrients. Thus, a mitogen-activated protein kinase-dependent \nmechanism regulates autophagy by controlling the biogenesis and partnership of \ntwo distinct cellular organelles.",
"Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is an important, highly \nconserved, regulator of cell growth. Ancient among the signals that regulate \nmTORC1 are nutrients. Amino acids direct mTORC1 to the surface of the late \nendosome/lysosome, where mTORC1 becomes receptive to other inputs. However, the \ninterplay between endosomes and mTORC1 is poorly understood. Here, we report the \ndiscovery of a network that links mTORC1 to a critical component of the late \nendosome/lysosome, the V-ATPase. In an unbiased screen, we found that mTORC1 \nregulated the expression of, among other lysosomal genes, the V-ATPases. mTORC1 \nregulates V-ATPase expression both in cells and in mice. V-ATPase regulation by \nmTORC1 involves a transcription factor translocated in renal cancer, TFEB. TFEB \nis required for the expression of a large subset of mTORC1 responsive genes. \nmTORC1 coordinately regulates TFEB phosphorylation and nuclear localization and \nin a manner dependent on both TFEB and V-ATPases, mTORC1 promotes endocytosis. \nThese data uncover a regulatory network linking an oncogenic transcription \nfactor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and \nendocytosis.",
"Canonical Wnt signaling plays an important role in development and disease, \nregulating transcription of target genes and stabilizing many proteins \nphosphorylated by glycogen synthase kinase 3 (GSK3). We observed that the MiT \nfamily of transcription factors, which includes the melanoma oncogene MITF \n(micropthalmia-associated transcription factor) and the lysosomal master \nregulator TFEB, had the highest phylogenetic conservation of three consecutive \nputative GSK3 phosphorylation sites in animal proteomes. This finding prompted \nus to examine the relationship between MITF, endolysosomal biogenesis, and Wnt \nsignaling. Here we report that MITF expression levels correlated with the \nexpression of a large subset of lysosomal genes in melanoma cell lines. MITF \nexpression in the tetracycline-inducible C32 melanoma model caused a marked \nincrease in vesicular structures, and increased expression of late endosomal \nproteins, such as Rab7, LAMP1, and CD63. These late endosomes were not \nfunctional lysosomes as they were less active in proteolysis, yet were able to \nconcentrate Axin1, phospho-LRP6, phospho-β-catenin, and GSK3 in the presence of \nWnt ligands. This relocalization significantly enhanced Wnt signaling by \nincreasing the number of multivesicular bodies into which the Wnt \nsignalosome/destruction complex becomes localized upon Wnt signaling. We also \nshow that the MITF protein was stabilized by Wnt signaling, through the novel \nC-terminal GSK3 phosphorylations identified here. MITF stabilization caused an \nincrease in multivesicular body biosynthesis, which in turn increased Wnt \nsignaling, generating a positive-feedback loop that may function during the \nproliferative stages of melanoma. The results underscore the importance of \nmisregulated endolysosomal biogenesis in Wnt signaling and cancer.",
"OBJECTIVE: Recent reports of a proatherogenic phenotype in mice with \nmacrophage-specific autophagy deficiency have renewed interest in the role of \nthe autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique \nability to process both exogenous material, including lipids and \nautophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to \nunderstand the effects of an atherogenic lipid environment on macrophage \nlysosomes and to evaluate novel ways to modulate this system.\nAPPROACH AND RESULTS: Using a variety of complementary techniques, we show that \noxidized low-density lipoproteins and cholesterol crystals, commonly encountered \nlipid species in atherosclerosis, lead to profound lysosomal dysfunction in \ncultured macrophages. Disruptions in lysosomal pH, proteolytic capacity, \nmembrane integrity, and morphology are readily seen. Using flow cytometry, we \nfind that macrophages isolated from atherosclerotic plaques also display \nfeatures of lysosome dysfunction. We then investigated whether enhancing \nlysosomal function can be beneficial. Transcription factor EB (TFEB) is the only \nknown transcription factor that is a master regulator of lysosomal biogenesis \nalthough its role in macrophages has not been studied. Lysosomal stress induced \nby chloroquine or atherogenic lipids leads to TFEB nuclear translocation and \nactivation of lysosomal and autophagy genes. TFEB overexpression in macrophages \nfurther augments this prodegradative response and rescues several deleterious \neffects seen with atherogenic lipid loading as evidenced by blunted lysosomal \ndysfunction, reduced secretion of the proinflammatory cytokine interleukin-1β, \nenhanced cholesterol efflux, and decreased polyubiquitinated protein \naggregation.\nCONCLUSIONS: Taken together, these data demonstrate that lysosomal function is \nmarkedly impaired in atherosclerosis and suggest that induction of a lysosomal \nbiogenesis program in macrophages has antiatherogenic effects.",
"Progranulin (PGRN) is known to play a role in the pathogenesis of \nneurodegenerative diseases. Recently, it has been demonstrated that patients \nwith the homozygous mutation in the GRN gene present with neuronal ceroid \nlipofuscinosis, and there is growing evidence that PGRN is related to lysosomal \nfunction. In the present study, we investigated the possible role of PGRN in the \nlysosomes of activated microglia in the cerebral cortex after traumatic brain \ninjury (TBI). We showed that the mouse GRN gene has two possible coordinated \nlysosomal expression and regulation (CLEAR) sequences that bind to transcription \nfactor EB (TFEB), a master regulator of lysosomal genes. PGRN was colocalized \nwith Lamp1, a lysosomal marker, and Lamp1-positive areas in GRN-deficient (KO) \nmice were significantly expanded compared with wild-type (WT) mice after TBI. \nExpression of all the lysosome-related genes examined in KO mice was \nsignificantly higher than that in WT mice. The number of activated microglia \nwith TFEB localized to the nucleus was also significantly increased in KO as \ncompared with WT mice. Since the TFEB translocation is regulated by the \nmammalian target of rapamycin complex 1 (mTORC1) activity in the lysosome, we \ncompared ribosomal S6 kinase 1 (S6K1) phosphorylation that reflects mTORC1 \nactivity. S6K1 phosphorylation in KO mice was significantly lower than that in \nWT mice. In addition, the number of nissl-positive and fluoro-jade B-positive \ncells around the injury was significantly decreased and increased, respectively, \nin KO as compared with WT mice. These results suggest that PGRN localized in the \nlysosome is involved in the activation of mTORC1, and its deficiency leads to \nincreased TFEB nuclear translocation with a resultant increase in lysosomal \nbiogenesis in activated microglia and exacerbated neuronal damage in the \ncerebral cortex after TBI.",
"In metazoans, lysosomes are the center for the degradation of macromolecules and \nplay a key role in a variety of cellular processes, such as autophagy, \nexocytosis and membrane repair. Defects of lysosomal pathways are associated \nwith lysosomal storage disorders and with several late onset neurodegenerative \ndiseases. We recently discovered the CLEAR (Coordinated Lysosomal Expression and \nRegulation) gene network and its master gene transcription factor EB (TFEB), \nwhich regulates lysosomal biogenesis and function. Here, we used a combination \nof genomic approaches, including ChIP-seq (sequencing of chromatin \nimmunoprecipitate) analysis, profiling of TFEB-mediated transcriptional \ninduction, genome-wide mapping of TFEB target sites and recursive expression \nmeta-analysis of TFEB targets, to identify 471 TFEB direct targets that \nrepresent essential components of the CLEAR network. This analysis revealed a \ncomprehensive system regulating the expression, import and activity of lysosomal \nenzymes that control the degradation of proteins, glycosaminoglycans, \nsphingolipids and glycogen. Interestingly, the CLEAR network appears to be \ninvolved in the regulation of additional lysosome-associated processes, \nincluding autophagy, exo- and endocytosis, phagocytosis and immune response. \nFurthermore, non-lysosomal enzymes involved in the degradation of essential \nproteins such as hemoglobin and chitin are also part of the CLEAR network. \nFinally, we identified nine novel lysosomal proteins by using the CLEAR network \nas a tool for prioritizing candidates. This study provides potential therapeutic \ntargets to modulate cellular clearance in a variety of disease conditions.",
"Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic \ninterior and are central to the autophagic, endocytic, or phagocytic pathway. In \ncontrast to its classical function as the waste management machinery, lysosomes \nare now considered to be an integral part of various cellular signaling \nprocesses. The diverse functionality of this single organelle requires a very \ncomplex and coordinated regulation of its activity with transcription factor EB \n(TFEB), a master regulator of lysosomal biogenesis, at its core. However, \nmechanisms by which TFEB is regulated are poorly understood. This study \ndemonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated \nreceptor (PPAR) α, alone and in conjunction with all-trans-retinoic acid is \ncapable of enhancing TFEB in brain cells. We also observed that PPARα, but not \nPPARβ and PPARγ, is involved in gemfibrozil-mediated up-regulation of TFEB. \nReporter assay and chromatin immunoprecipitation studies confirmed the \nrecruitment of retinoid X receptor α, PPARα, and PGC1α on the PPAR-binding site \non the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB \ncaused an increase in lysosomal protein and the lysosomal abundance in cell. \nCollectively, this study reinforces the link between lysosomal biogenesis and \nlipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of \ntherapeutic value in the treatment of lysosomal storage disorders in which \nautophagy-lysosome pathway plays an important role."
] | nan |
5fdb43aea43ad3127800002b | [
25940801,
19796237,
23382991,
26267538,
23024276,
29973462,
29382715,
16751774,
20581311
] | train | Which transcription factor regulates emergency granulopoiesis? | factoid | The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) plays critical roles in the differentiation and proliferation of hematopoietic stem cells. | c/EBPβ or c/EBPbeta | [
"Steady-state hematopoiesis responds to extracellular stimuli to meet changing \ndemands and also to pathologically altered intracellular signaling. Granulocyte \nproduction increases following infection or in response to cytokine stimulation, \nand activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription \nfactor is required for such stress-induced granulopoiesis, whereas C/EBPα plays \na critical role in maintaining steady-state granulopoiesis. Different roles of \nthese C/EBP transcription factors in different modes of hematopoiesis are \nevolutionally conserved from zebrafish to humans. In addition to reactions \nagainst infections, C/EBPβ is responsible for cancer-driven myelopoiesis, which \npromotes cancer progression, at least in part, by abrogating the immune response \nin the cancer microenvironment. The BCR-ABL fusion protein activates \nemergency-specific pathway of granulopoiesis by upregulating C/EBPβ. This in \nturn causes chronic phase chronic myeloid leukemia, which is characterized by \nmyeloid expansion. The C/EBPβ transcription factor also plays a role in other \nhematological malignancies of both myeloid and lymphoid lineage origin. Thus, \nelucidation of the upstream and downstream networks surrounding C/EBPβ will lead \nto the development of novel therapeutic strategies for diseases mediated by \nnon-steady-state hematopoiesis.",
"Severe congenital neutropenia (CN) is a heterogeneous hematopoietic syndrome \nwith a typical \"maturation arrest\" of granulocytic precursors at the \npromyelocytic stage, inherited in an autosomal dominant or recessive manner. \nIntriguingly, CN patients have the same bone marrow and blood phenotypes \nirrespective of inheritance. This suggests that mutations in various genes may \nlead to the dysregulation of the common myeloid transcription factor(s) in CN. \nTo the extensively studied myeloid-specific transcription factors belong \nCCAAT/enhancer-binding proteins (C/EBPs) (-alpha, -beta, -epsilon) and PU.1. The \nrelative levels of PU.1 and C/EBPalpha in granulocytic-macrophage progenitors \nhave been suggested to regulate monocyte versus neutrophil cell-fate choice. In \nCN patients, the myelopoietic maturation program is sharply shifted toward \nmonocytopoiesis, with increased levels of monocytes and no granulocytes in the \nperipheral blood. We found that in myeloid cells from CN patients C/EBPalpha and \nits target gene inhibitor of DNA binding 1 (Id1) are abrogated due to a lack of \nlymphoid enhancer-binding factor 1 (LEF-1) expression but PU.1 is slightly \nupregulated. Based on these findings, we conclude that in LEF-1-deficient \nmyeloid cells from CN patients misbalanced C/EBPalpha/Id1:PU.1 ratio with a \nstrong shift toward PU.1 could play a decisive role in the improper regulation \nof myelopoiesis with defective granulocytopoiesis and elevated monocytic \ndifferentiation. Recently, we identified nicotinamide phosphoribosyltransferase \n(NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an \nessential enzyme mediating granulocyte colony-stimulating factor \n(G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with \nCN. Since CN patients respond to G-CSF treatment even in the absence of LEF-1 \nand C/EBPalpha, we conclude that treatment of CN patients with pharmacological \ndoses of G-CSF activates NAMPT/NAD(+)/SIRT1-dependent \"emergency\" granulopoiesis \nvia C/EBPbeta.",
"In contrast to the definitive role of the transcription factor, CCAAT/Enhancer \nbinding protein α (C/EBPα), in steady-state granulopoiesis, previous findings \nhave suggested that granulopoiesis during emergency situations, such as \ninfection, is dependent on C/EBPβ. In this study, a novel lentivirus-based \nreporter system was developed to elucidate the molecular switch required for \nC/EBPβ-dependency. The results demonstrated that two cyclic AMP responsive \nelements (CREs) in the proximal promoter region of C/EBPβ were involved in the \npositive regulation of C/EBPβ transcription during granulocyte-macrophage \ncolony-stimulating factor (GM-CSF)-induced differentiation of bone marrow cells. \nIn addition, the transcripts of CRE binding (CREB) family proteins were readily \ndetected in hematopoietic stem/progenitor cells. CREB was upregulated, \nphosphorylated and bound to the CREs in response to GM-CSF stimulation. \nRetroviral transduction of a dominant negative CREB mutant reduced C/EBPβ mRNA \nlevels and significantly impaired the proliferation/differentiation of \ngranulocyte precursors, while a constitutively active form of CREB facilitated \nC/EBPβ transcription. These data suggest that CREB proteins are involved in the \nregulation of granulopoiesis via C/EBPβ upregulation.",
"Cancer-driven granulo-monocytopoiesis stimulates expansion of tumor promoting \nmyeloid populations, mostly myeloid-derived suppressor cells (MDSCs) and \ntumor-associated macrophages (TAMs). We identified subsets of MDSCs and TAMs \nbased on the expression of retinoic-acid-related orphan receptor (RORC1/RORγ) in \nhuman and mouse tumor bearers. RORC1 orchestrates myelopoiesis by suppressing \nnegative (Socs3 and Bcl3) and promoting positive (C/EBPβ) regulators of \ngranulopoiesis, as well as the key transcriptional mediators of myeloid \nprogenitor commitment and differentiation to the monocytic/macrophage lineage \n(IRF8 and PU.1). RORC1 supported tumor-promoting innate immunity by protecting \nMDSCs from apoptosis, mediating TAM differentiation and M2 polarization, and \nlimiting tumor infiltration by mature neutrophils. Accordingly, ablation of \nRORC1 in the hematopoietic compartment prevented cancer-driven myelopoiesis, \nresulting in inhibition of tumor growth and metastasis.",
"Granulopoiesis is tightly regulated to meet host demands during both \n\"steady-state\" and \"emergency\" situations, such as infections. The transcription \nfactor CCAAT/enhancer binding protein β (C/EBPβ) plays critical roles in \nemergency granulopoiesis, but the precise developmental stages in which C/EBPβ \nis required are unknown. In this study, a novel flow cytometric method was \ndeveloped that successfully dissected mouse bone marrow cells undergoing \ngranulopoiesis into five distinct subpopulations (#1-5) according to their \nlevels of c-Kit and Ly-6G expression. After the induction of candidemia, rapid \nmobilization of mature granulocytes and an increase in early granulocyte \nprecursors accompanied by cell cycle acceleration was followed by a gradual \nincrease in granulocytes originating from the immature populations. Upon \ninfection, C/EBPβ was upregulated at the protein level in all the granulopoietic \nsubpopulations. The rapid increase in immature subpopulations #1 and #2 observed \nin C/EBPβ knockout mice at 1 d postinfection was attenuated. Candidemia-induced \ncell cycle acceleration and proliferation of hematopoietic stem/progenitors were \nalso impaired. Taken together, these data suggest that C/EBPβ is involved in the \nefficient amplification of early granulocyte precursors during \ncandidemia-induced emergency granulopoiesis.",
"Under stress conditions such as infection, inflammation, and hematopoietic \nrecovery following chemotherapy or transplantation, the hematopoietic system is \nrequired to meet the increasing demands, especially from myeloid cells. \nTherefore, an understanding of the molecular mechanism underlying stress \nhematopoiesis is clinically imperative. We previously showed that C/EBPβ, which \nis a transcription factor required for emergency granulopoiesis, plays a pivotal \nrole at the level of hematopoietic stem/progenitor cells under stress \nconditions. Upon exposure to stress, the C/EBPβ protein is upregulated in the \nhematopoietic stem cells. A close examination of C/EBPβ knockout mice revealed \nthat C/EBPβ regulates the proliferation and differentiation of hematopoietic \nstem cells at the cost of the self-renewing activity. Further elucidation of the \nfunctions and regulation of C/EBPβ in hematopoietic stem cells will facilitate \nan understanding of stress hematopoiesis.",
"Interferon consensus sequence-binding protein (Icsbp) is required for \nterminating emergency granulopoiesis, an episodic event responsible for \ngranulocyte production in response to infections and a key component of the \ninnate immune response. Icsbp inhibits the expression of Stat3 and C/ebpβ, \ntranscription factors essential for initiating and sustaining granulopoiesis, \nand activates transcription of Fanconi C (FANCC), a DNA repair protein. In prior \nstudies, we noted accelerated bone marrow failure in Fancc-/- mice undergoing \nmultiple episodes of emergency granulopoiesis, associated with apoptosis of bone \nmarrow cells with unrepaired DNA damage. Additionally, we found increased \nexpression of Fanconi C and F proteins during emergency granulopoiesis. These \nfindings suggest that Icsbp protects the bone marrow from DNA damage by \nincreasing activity of the Fanconi DNA repair pathway, but the mechanisms for \nFANCC activation during initiation of emergency granulopoiesis are unclear. In \nthis study, we observed that Stat3 and C/ebpβ activate FANCC transcription and \ncontribute to DNA repair. Our findings indicate that FancC expression is \nincreased during Stat3- and C/ebpβ-induced initiation of emergency \ngranulopoiesis by these transcription factors and is maintained through \ntermination by Icsbp. Our work reveals that Stat3- and C/ebpβ-mediated FancC \nexpression is a critical component for initiating and sustaining key innate \nimmune responses.",
"During 'emergency' situations such as infections, host defense requires rapid \nmobilization of bone marrow granulocyte progenitors. 'Steady-state' \ngranulopoiesis is absolutely dependent on the C/EBPalpha transcription factor, \nbut the transcriptional mechanisms underlying emergency granulopoiesis remain \nunclear. Here we show that large numbers of granulocytes were generated from \nC/EBPalpha-deficient progenitors after cytokine stimulation in vivo. Cytokine \ntreatment or fungal infection induced upregulation of C/EBPbeta but not \nC/EBPalpha or C/EBPepsilon transcripts in granulocyte progenitors, and \nC/EBPbeta-deficient progenitors showed decreased emergency-induced \ngranulopoiesis in vitro and in vivo. C/EBPbeta inhibited proliferation less \nseverely than did C/EBPalpha. These data suggest a critical function for \nC/EBPbeta in emergency granulopoiesis, which demands both differentiation and \nproliferation of granulocyte precursors.",
"Granulocyte colony-stimulating factor (G-CSF) mediates \"emergency\" \ngranulopoiesis during infection, a process that is mimicked by clinical G-CSF \nuse, yet we understand little about the intracellular signaling cascades that \ncontrol demand-driven neutrophil production. Using a murine model with \nconditional deletion of signal transducer and activator of transcription 3 \n(STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of \nSTAT3 function in the emergency granulopoiesis response to G-CSF administration \nor infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF \nsignaling in vivo. Our results show that STAT3 deficiency renders hematopoietic \nprogenitor cells and myeloid precursors refractory to the growth-promoting \nfunctions of G-CSF or L monocytogenes infection. STAT3 is necessary for \naccelerating granulocyte cell-cycle progression and maturation in response to \nG-CSF. STAT3 directly controls G-CSF-dependent expression of \nCCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency \ngranulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through \ninteractions with the c-myc promoter that control the duration of C/EBPα \noccupancy during demand-driven granulopoiesis. These results place STAT3 as an \nessential mediator of emergency granulopoiesis by its regulation of \ntranscription factors that direct G-CSF-responsive myeloid progenitor expansion."
] | nan |
54fb4b34d176fff445000001 | [
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9809067,
9659924,
10747925,
10024886,
18420790,
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19944700,
8548797,
9770462,
10848607
] | train | Which transcription factors (TFs) participate in the formation of the interferon-beta (IFN-b) enhanceosome? | list | Transcriptional activation of the IFN beta gene in response to virus infection requires the assembly of an enhanceosome, consisting of the transcriptional activators NF-kappa B, IRF1, ATF2/c-Jun, and the architectural protein HMG I(Y). Transcriptional activation of the human interferon-beta (IFN-beta) gene by virus infection requires the assembly of a higher order nucleoprotein complex, the enhanceosome, which consists of the transcriptional activators NF-kappa B (p50/p65), ATF-2/c-jun, IRF-3 and IRF-7, architectural protein HMGI(Y), and the coactivators p300 and CBP. | ['NF-kappa B (p50/p65)', 'ATF-2', 'c-jun', 'IRF-3', 'IRF-7', 'IRF-1'] | [
"A functional interferon-beta gene enhanceosome was assembled in vitro using the \npurified recombinant transcriptional activator proteins ATF2/c-JUN, IRF1, and \np50/p65 of NF-kappa B. Maximal levels of transcriptional synergy between these \nactivators required the specific interactions with the architectural protein HMG \nI(Y) and the correct helical phasing of the binding sites of these proteins on \nthe DNA helix. Analyses of the in vitro assembled enhanceosome revealed that the \ntranscriptional synergy is due, at least in part, to the cooperative assembly \nand stability of the complex. Reconstitution experiments showed that the \nformation of a stable enhanceosome-dependent preinitiation complex require \ncooperative interactions between the enhanceosome; the general transcription \nfactors TFID, TFIIA, and TFIIB; and the cofactor USA. These studies provide a \ndirect biochemical demonstration of the importance of the structure and function \nof natural multicomponent transcriptional enhancer complexes in gene regulation.",
"Transcriptional activation of the interferon-beta (IFN-beta) gene requires \nassembly of an enhanceosome containing the transcription factors ATF-2/c-Jun, \nIRF-3/IRF-7, NF-kappaB and HMGI(Y). These factors cooperatively bind a composite \nDNA site and activate expression of the IFN-beta gene. The 3.0 A crystal \nstructure of the DNA-binding domains of ATF-2/c-Jun and two IRF-3 molecules in a \ncomplex with 31 base pairs (bp) of the PRDIV-PRDIII region of the IFN-beta \nenhancer shows that association of the four proteins with DNA creates a \ncontinuous surface for the recognition of 24 bp. The structure, together with in \nvitro binding studies and protein mutagenesis, shows that protein-protein \ninteractions are not critical for cooperative binding. Instead, cooperativity \narises mainly through nucleotide sequence-dependent structural changes in the \nDNA that allow formation of complementary DNA conformations. Because the binding \nsites overlap on the enhancer, the unit of recognition is the entire nucleotide \nsequence, not the individual subsites.",
"The transcriptional coactivators CBP and P/CAF are required for activation of \ntranscription from the IFN beta enhanceosome. We show that CBP and P/CAF \nacetylate HMG I(Y), the essential architectural component required for \nenhanceosome assembly, at distinct lysine residues, causing distinct effects on \ntranscription. Thus, in the context of the enhanceosome, acetylation of HMG I by \nCBP, but not by P/CAF, leads to enhanceosome destabilization and disassembly. We \ndemonstrate that acetylation of HMG I(Y) by CBP is essential for turning off IFN \nbeta gene expression. Finally, we show that the acetyltransferase activities of \nCBP and P/CAF modulate both the strength of the transcriptional response and the \nkinetics of virus-dependent activation of the IFN beta gene.",
"Transcriptional activation of the IFN beta gene in response to virus infection \nrequires the assembly of an enhanceosome, consisting of the transcriptional \nactivators NF-kappa B, IRF1, ATF2/c-Jun, and the architectural protein HMG I(Y). \nThe level of transcription generated by all of these activators is greater than \nthe sum of the levels generated by individual factors, a phenomenon designated \ntranscriptional synergy. We demonstrate that this synergy, in the context of the \nenhanceosome, requires a new protein-protein interaction domain in the p65 \nsubunit of NF-kappa B. Transcriptional synergy requires recruitment of the \nCBP/p300 coactivator to the enhanceosome, via a new activating surface assembled \nfrom the novel p65 domain and the activation domains of all of the activators. \nDeletion, substitution, or rearrangement of any one of the activation domains in \nthe context of the enhanceosome decreases both recruitment of CBP and \ntranscriptional synergy.",
"Small molecules that modulate specific protein functions are valuable tools for \ndissecting complex signaling pathways. Here, we identified a small molecule that \ninduces the assembly of the interferon-beta (IFN-beta) enhanceosome by \nstimulating all the enhancer-binding activator proteins: ATF2/c-JUN, IRF3, and \np50/p65 of NF-kappaB. This compound stimulates mitogen-activated protein kinase \nkinase kinase 1 (MEKK1), which is a member of a family of proteins involved in \nstress-mediated signaling pathways. Consistent with this, MEKK1 activates IRF3 \nin addition to ATF2/c-JUN and NF-kappaB for the assembly of the IFN-beta \nenhanceosome. MEKK1 activates IRF3 through the c-JUN amino-terminal kinase (JNK) \npathway but not the p38 and IkappaB kinase (IKK) pathway. Taken together with \nprevious observations, these results implicate that, for the assembly of an \nIFN-beta enhanceosome, MEKK1 can induce IRF3 and ATF2/c-JUN through the JNK \npathway, whereas it can induce NF-kappaB through the IKK pathway. Thus, specific \nMEKK family proteins may be able to integrate some of multiple signal \ntransduction pathways leading to the specific activation of the IFN-beta \nenhanceosome.",
"Transcriptional activation of the human interferon-beta (IFN-beta) gene by virus \ninfection requires the assembly of a higher order nucleoprotein complex, the \nenhanceosome, which consists of the transcriptional activators NF-kappa B \n(p50/p65), ATF-2/c-jun, IRF-3 and IRF-7, architectural protein HMGI(Y), and the \ncoactivators p300 and CBP. In this report, we show that virus infection of cells \nresults in a dramatic hyperacetylation of histones H3 and H4 that is localized \nto the IFN-beta promoter. Furthermore, expressing a truncated version of IRF-3, \nwhich lacks a p300/CBP interaction domain, suppresses both histone \nhyperacetylation and activation of the IFN-beta gene. Thus, coactivator-mediated \nlocalized hyperacetylation of histones may play a crucial role in inducible gene \nexpression.",
"We have investigated beta interferon (IFN-beta) and IFN-alpha4 gene expression \nand activation of related transcription factors in mouse cytomegalovirus \n(MCMV)-infected fibroblasts. mRNA analysis demonstrated an initial phase of IFN \ngene induction upon MCMV infection, which was followed by a sustained \nMCMV-mediated simultaneous downregulation of IFN-beta and IFN-alpha4 gene \nexpression. The induction of IFN transcription resulted from the activation of \nthe components of the IFN-beta enhanceosome, i.e. IFN regulatory factor (IRF) 3, \nnuclear factor (NF)-kappaB, activating transcription factor (ATF)-2 and c-Jun. \nActivation of the transcription factors occurred rapidly and in a sequential \norder upon infection, but only lasted a while. As a consequence, IFN-alpha/beta \ngene expression became undetectable 6 h post-infection and throughout the MCMV \nreplication cycle. This effect is based on an active interference since \nrestimulation of IFN gene induction by further external stimuli (e.g. Sendai \nvirus infection) was completely abolished. This inhibition required MCMV gene \nexpression and was not observed in cells infected with UV-inactivated MCMV \nvirions. The efficiency of inhibition is achieved by a concerted blockade of \nIkappaBalpha degradation and a lack of nuclear accumulation of IRF3 and \nATF-2/c-Jun. Using an MCMV mutant lacking pM27, a signal transducer and \nactivator of transcription (STAT) 2-specific inhibitor of Jak/STAT signalling, \nwe found that the initial phase of IFN induction and the subsequent inhibition \ndoes not depend on the positive-IFN feedback loop. Our findings indicate that \nthe MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a \nlarge arsenal of inhibitory mechanisms targeting each pathway that contributes \nto the multiprotein enhanceosome complex.",
"Transcriptional activation of the virus inducible enhancer of the human \ninterferon-beta (IFN-beta) gene in response to virus infection requires the \nassembly of an enhanceosome, consisting of the transcriptional activators \nNF-kappaB, ATF-2/c-Jun, IRFs and the architectural protein of the mammalian high \nmobility group I(Y) [HMG I(Y)]. Here, we demonstrate that the first step in \nenhanceosome assembly, i.e. HMG I(Y)-dependent recruitment of NF-kappaB and \nATF-2/c-Jun to the enhancer, is facilitated by discrete regions of HMG I and is \nmediated by allosteric changes induced in the DNA by HMG I(Y) and not by \nprotein-protein interactions between HMG I(Y) and these proteins. However, we \nshow that completion of the enhanceosome assembly process requires \nprotein-protein interactions between HMG I(Y) and the activators. Finally, we \ndemonstrate that once assembled, the IFN-beta enhanceosome is an unusually \nstable nucleoprotein structure that can activate transcription at high levels by \npromoting multiple rounds of reinitiation of transcription.",
"The dimer formed by the ATF-2 and c-Jun transcription factors is one of the main \ncomponents of the human interferon-beta enhanceosome. Although these two \ntranscription factors are able to form two homodimers and one heterodimer, it is \nmainly the heterodimer that participates in the formation of this enhanceosome, \nbinding specifically to the positive regulatory domain IV (PRDIV) site of the \nenhancer DNA. To understand this surprising advantage of the heterodimer, we \ninvestigated the association of these transcription factors using fragments \ncontaining the basic DNA-recognition segment and the basic leucine zipper domain \n(bZIP). It was found that the probability of forming the hetero-bZIP \nsignificantly exceeds the probability of forming homo-bZIPs, and that the \nhetero-bZIP interacts more strongly with the PRDIV site of the interferon-beta \nenhancer, especially in the orientation that places the folded ATF-2 basic \nsegment in the upstream half of this asymmetric site. The effect of salt on the \nformation of the ATF-2/c-Jun dimer and on its ability to bind the target PRDIV \nsite showed that electrostatic interactions between the charged groups of these \nproteins and with DNA play an essential role in the formation of the asymmetric \nATF-2/c-Jun/PRDIV complex.",
"We present evidence that transcriptional activation of the human interferon-beta \n(IFN beta) gene requires the assembly of a higher order transcription enhancer \ncomplex (enhanceosome). This multicomponent complex includes at least three \ndistinct transcription factors and the high mobility group protein HMG I(Y). \nBoth the in vitro assembly and in vivo transcriptional activity of this complex \nrequire a precise helical relationship between individual transcription \nfactor-binding sites. In addition, HMG I(Y), which binds specifically to three \nsites within the enhancer, promotes cooperative binding of transcriptional \nfactors in vitro and is required for transcriptional synergy between these \nfactors in vivo. Thus, HMG I(Y) plays an essential role in the assembly and \nfunction of the IFN beta gene enhanceosome.",
"The transcriptional activity of an in vitro assembled human interferon-beta gene \nenhanceosome is highly synergistic. This synergy requires five distinct \ntranscriptional activator proteins (ATF2/c-JUN, interferon regulatory factor 1, \nand p50/p65 of NF-kappaB), the high mobility group protein HMG I(Y), and the \ncorrect alignment of protein-binding sites on the face of the DNA double helix. \nHere, we investigate the mechanisms of enhanceosome-dependent transcriptional \nsynergy during preinitiation complex assembly in vitro. We show that the \nstereospecific assembly of the enhanceosome is critical for the efficient \nrecruitment of TFIIB into a template-committed TFIID-TFIIA-USA (upstream \nstimulatory activity complex) and for the subsequent recruitment of the RNA \npolymerase II holoenzyme complex. In addition, we provide evidence that \nrecruitment of the holoenzyme by the enhanceosome is due, at least in part, to \ninteractions between the enhanceosome and the transcriptional coactivator CREB, \ncAMP responsive element binding protein (CBP). These studies reveal a unique \nrole of enhanceosomes in the cooperative assembly of the transcription machinery \non the human interferon-beta promoter.",
"Heterodimeric transcription factors, including the basic region-leucine zipper \n(bZIP) protein ATF-2-c-jun, are well-characterized components of an enhanceosome \nthat mediates virus induction of the human beta interferon (IFN-beta) gene. Here \nwe report that within the IFN-beta enhanceosome the ATF-2-c-jun heterodimer \nbinds in a specific orientation, which is required for assembly of a complex \nbetween ATF-2-c-jun and interferon regulatory factor 3 (IRF-3). We demonstrate \nthat correct orientation of the ATF-2-c-jun binding site is required for virus \ninduction of the IFN-beta gene and for IRF-3-dependent activation of a composite \nATF-2- c-jun-IRF site in the IFN-beta promoter. We also show that in vitro the \nDNA-bound ATF-2-c-jun heterodimer adopts a fixed orientation upon the binding of \nIRF-3 at an adjacent site in the IFN-beta enhancer and that the DNA-binding \ndomain of IRF-3 is sufficient to mediate this effect. In addition, we show that \nthe DNA-binding domain of ATF-2 is necessary and sufficient for selective \nprotein-protein interactions with IRF-3. Strikingly, in vivo chromatin \nimmunoprecipitation experiments with IFN-beta reporter constructs reveal that \nrecruitment of IRF-3 to the IFN-beta promoter upon virus infection is dependent \non the orientation of the ATF-2-c-jun heterodimer binding site. These \nobservations demonstrate functional and physical cooperativity between the bZIP \nand IRF transcription factor families and illustrate the critical role of \nheterodimeric transcription factors in formation of the IFN-beta enhanceosome."
] | ['http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016899', 'http://www.uniprot.org/uniprot/IFN_ANAPL', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0034206', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014157', 'http://www.biosemantics.org/jochem#4250284'] |
5319abe4b166e2b80600002e | [
17615296,
22406531,
22562246,
22266854,
19581928,
22833386,
24297167,
15674322,
22727060,
19295128,
18286686,
20735391
] | train | Which transcription factors are involved in E-cadherin repression during EMT? | list | Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal transition (EMT) in embryonic development and cancer progression. Overexpression of Snail1 (Snail), Snail2 (Slug), Zeb1, Twist, SIP1 and DeltaEF1 have been found to mediate E-cadherin repression, induce the mesenchymal markers vimentin and fibronectin, and finally promote the migratory and invasive capabilities in cancer cells. | ['Snail1 (Snail)', 'Snail2 (Slug)', 'Zeb1', 'Twist', 'SIP1', 'DeltaEF1'] | [
"Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression \nand embryonic development, is induced by transforming growth factor (TGF)-beta \nin mouse mammary NMuMG epithelial cells. Id proteins have previously been \nreported to inhibit major features of TGF-beta-induced EMT. In this study, we \nshow that expression of the deltaEF1 family proteins, deltaEF1 (ZEB1) and SIP1, \nis gradually increased by TGF-beta with expression profiles reciprocal to that \nof E-cadherin. SIP1 and deltaEF1 each dramatically down-regulated the \ntranscription of E-cadherin in NMuMG cells through direct binding to the \nE-cadherin promoter. Silencing of the expression of both SIP1 and deltaEF1, but \nnot either alone, completely abolished TGF-beta-induced E-cadherin repression. \nHowever, expression of mesenchymal markers, including fibronectin, N-cadherin, \nand vimentin, was not affected by knockdown of SIP1 and deltaEF1. \nTGF-beta-induced the expression of Ets1, which in turn activated deltaEF1 \npromoter activity. Moreover, up-regulation of SIP1 and deltaEF1 expression by \nTGF-beta was suppressed by knockdown of Ets1 expression. In addition, Id2 \nsuppressed the TGF-beta- and Ets1-induced up-regulation of deltaEF1. Taken \ntogether, these findings suggest that the deltaEF1 family proteins, SIP1 and \ndeltaEF1, are necessary, but not sufficient, for TGF-beta-induced EMT and that \nEts1 induced by TGF-beta may function as an upstream transcriptional regulator \nof SIP1 and deltaEF1.",
"Breast cancers are highly heterogeneous but can be grouped into subtypes based \non several criteria, including level of expression of certain markers. \nClaudin-low breast cancer (CLBC) is associated with early metastasis and \nresistance to chemotherapy, while gene profiling indicates it is characterized \nby the expression of markers of epithelial-mesenchymal transition (EMT) - a \nphenotypic conversion linked with metastasis. Although the epigenetic program \ncontrolling the phenotypic and cellular plasticity of EMT remains unclear, one \ncontributor may be methylation of the E-cadherin promoter, resulting in \ndecreased E-cadherin expression, a hallmark of EMT. Indeed, reduced E-cadherin \noften occurs in CLBC and may contribute to the early metastasis and poor patient \nsurvival associated with this disease. Here, we have determined that methylation \nof histone H3 on lysine 9 (H3K9me2) is critical for promoter DNA methylation of \nE-cadherin in three TGF-β-induced EMT model cell lines, as well as in CLBC cell \nlines. Further, Snail interacted with G9a, a major euchromatin methyltransferase \nresponsible for H3K9me2, and recruited G9a and DNA methyltransferases to the \nE-cadherin promoter for DNA methylation. Knockdown of G9a restored E-cadherin \nexpression by suppressing H3K9me2 and blocking DNA methylation. This resulted in \ninhibition of cell migration and invasion in vitro and suppression of tumor \ngrowth and lung colonization in in vivo models of CLBC metastasis. Our study not \nonly reveals a critical mechanism underlying the epigenetic regulation of EMT \nbut also paves a way for the development of new treatment strategies for CLBC.",
"Expression of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), \nis often lost due to promoter DNA methylation in basal-like breast cancer \n(BLBC), which contributes to the metastatic advantage of this disease; however, \nthe underlying mechanism remains unclear. Here, we identified that Snail \ninteracted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major \nmethyltransferase responsible for H3K9me3 that intimately links to DNA \nmethylation. We demonstrated that the SNAG domain of Snail and the SET domain of \nSuv39H1 were required for their mutual interactions. We found that H3K9me3 and \nDNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We \nshowed that Snail interacted with Suv39H1 and recruited it to the E-cadherin \npromoter for transcriptional repression. Knockdown of Suv39H1 restored \nE-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in \nthe inhibition of cell migration, invasion and metastasis of BLBC. Our study not \nonly reveals a critical mechanism underlying the epigenetic regulation of EMT, \nbut also paves a way for the development of new treatment strategies against \nthis disease.",
"Endometrial carcinoma (EC) is the most frequent among infiltrating tumors of the \nfemale genital tract, with myometrial invasion representing an increase in the \nrate of recurrences and a decrease in survival. We have previously described \nETV5 transcription factor associated with myometrial infiltration in human ECs. \nIn this work, we further investigated ETV5 orchestrating downstream effects to \nconfer the tumor the invasive capabilities needed to disseminate in the early \nstages of EC dissemination. Molecular profiling evidenced ETV5 having a direct \nrole on epithelial-to-mesenchymal transition (EMT). In particular, ETV5 \nmodulated Zeb1 expression and E-Cadherin repression leading to a complete \nreorganization of cell-cell and cell-substrate contacts. ETV5-promoted EMT \nresulted in the acquisition of migratory and invasive capabilities in \nendometrial cell lines. Furthermore, we identified the lipoma-preferred partner \nprotein as a regulatory partner of ETV5, acting as a sensor for extracellular \nsignals promoting tumor invasion. All together, we propose ETV5-transcriptional \nregulation of the EMT process through a crosstalk with the tumor surrounding \nmicroenvironment, as a principal event initiating EC invasion.",
"Breast tumor interleukin-6 (IL-6) levels increase with tumor grade, and elevated \nserum IL-6 correlates with poor breast cancer patient survival. \nEpithelial-mesenchymal transition (EMT) phenotypes such as impaired E-cadherin \nexpression or aberrant Vimentin induction are associated with enhanced \nmetastasis and unfavorable clinical outcome in breast cancer. Despite this fact, \nfew tumor microenvironment-derived extracellular signaling factors capable of \nprovoking such a phenotypic transition have been identified. In this study, we \nshowed that IL-6 promoted E-cadherin repression among a panel of estrogen \nreceptor-alpha-positive human breast cancer cells. Furthermore, ectopic stable \nIL-6 expressing MCF-7 breast adenocarcinoma cells (MCF-7(IL-6)) exhibited an EMT \nphenotype characterized by impaired E-cadherin expression and induction of \nVimentin, N-cadherin, Snail and Twist. MCF-7(IL-6) cells formed xenograft tumors \nthat displayed loss of E-cadherin, robust Vimentin induction, increased \nproliferative indices, advanced tumor grade and undifferentiated histology. \nFinally, we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells \nthat constitutively express Twist, a metastatic regulator and direct \ntranscriptional repressor of E-cadherin. To our knowledge, this is the first \nstudy that shows IL-6 as an inducer of an EMT phenotype in breast cancer cells \nand implicates its potential to promote breast cancer metastasis.",
"The proliferation, directional migration to the vitreous and \nepithelial-mesenchymal transition (EMT) of quiescent, differentiated retinal \npigment epithelium (RPE) cells is a major feature in the development of \nproliferative vitreoretinopathy (PVR) following exposure of the \nimmuno-privileged eye niche to serum components, thrombin among them. We have \npreviously documented thrombin induction of RPE cell proliferation and \nmigration. We here analyzed the effect of thrombin on the E/N cadherin switch, a \nhallmark of EMT. Results show that thrombin induces the specific repression of \nepithelial E-cadherin gene transcription, alongside with the up-regulation of \nmesenchymal N-cadherin protein in RPE cells. We demonstrate, for the first time, \nthat thrombin induces E-cadherin repression by stimulating snail-2 (SLUG) \ntranscription factor expression, and the concomitant up-regulation of N-cadherin \nthrough the transcription-independent increase in protein translation promoted \nby PI3K/PKC-ζ/mTOR signaling. Our present findings suggest that the activation \nof protease-activated receptor-1 (PAR-1) by thrombin induces EMT of RPE cells, \nfurther supporting a central role for thrombin in PVR pathogenesis.",
"Snail1 (Snail) and Snail2 (Slug) are transcription factors that share a similar \nDNA binding structure of four and five C2H2 zinc finger motifs (ZF), \nrespectively. Both factors bind specifically to a subset of E-box motifs \n(E2-box: CAGGTG/CACCTG) in target promoters like the E-cadherin promoter and are \nkey mediators of epithelial-to-mesenchymal transition (EMT). However, there are \ndifferences in the biological actions, in binding affinities to E-cadherin \npromoter, and in the target genes of Snail1 and Snail2, although the molecular \nbases are presently unknown. In particular, the role of each Snail1 and Snail2 \nZF in the binding to E-boxes and in EMT induction has not been previously \nexplored. We have approached this question by modeling Snail1 and Snail2 \nprotein-DNA interactions and through mutational and functional assays of \ndifferent ZFs. Results show that Snail1 efficient repression and binding to \nhuman and mouse E-cadherin promoter as well as EMT-inducing ability require \nintact ZF1 and ZF2, while for Snail2, either ZF3 or ZF4 is essential for those \nfunctions. Furthermore, the differential distribution of E2-boxes in mouse and \nhuman E-cadherin promoters also contributes to the differential Snail factor \nactivity. These data indicate a non-equivalent role of Snail1 and Snail2 ZFs in \ngene repression, contributing to the elucidation of the molecular differences \nbetween these important EMT regulators.",
"Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal \ntransition (EMT) in embryonic development and cancer progression. Using the \nEpFosER mammary tumour model we show that during EMT, upregulation of the \ntranscriptional regulator deltaEF1 coincided with transcriptional repression of \nE-cadherin. Ectopic expression of deltaEF1 in epithelial cells was sufficient to \ndownregulate E-cadherin and to induce EMT. Analysis of E-cadherin promoter \nactivity and chromatin immunoprecipitation identified deltaEF1 as direct \ntranscriptional repressor of E-cadherin. In human cancer cells, transcript \nlevels of deltaEF1 correlated directly with the extent of E-cadherin repression \nand loss of the epithelial phenotype. The protein was enriched in nuclei of \nhuman cancer cells and physically associated with the E-cadherin promoter. RNA \ninterference-mediated downregulation of deltaEF1 in cancer cells was sufficient \nto derepress E-cadherin expression and restore cell to cell adhesion, suggesting \nthat deltaEF1 is a key player in late stage carcinogenesis.",
"Snail family proteins regulate transcription of molecules for cell-cell adhesion \nduring epithelial-mesenchymal transition (EMT). Based on putative glycogen \nsynthase kinase 3β (GSK-3β) phosphorylation sites within the Slug/Snail2, we \nexplored the significance of GSK-3β-mediated phosphorylation in Slug/Snail2 \nexpression during EMT. Mutation of the putative GSK-3β phosphorylation sites \n(S92/96A or S100/104A) enhanced the Slug/Snail2-mediated EMT properties of \nE-cadherin repression and vimentin induction, compared with wild-type \nSlug/Snail2. S92/96A mutation inhibited degradation of Slug/Snail2 and S100/104A \nmutation extended nuclear stabilization. Inhibition of GSK-3β activity caused \nsimilar effects, as did the phosphorylation mutations. Thus, our study suggests \nthat GSK-3β-mediated phosphorylation of Slug/Snail2 controls its turnover and \nlocalization during EMT.",
"Functional loss of the cell-cell adhesion molecule E-cadherin is an essential \nevent for epithelial-mesenchymal transition (EMT), a process that allows cell \nmigration during embryonic development and tumour invasion. In most carcinomas, \ntranscriptional repression has emerged as the main mechanism responsible for \nE-cadherin downregulation. Here, we report the identification of class I bHLH \nfactor E2-2 (TCF4/ITF2) as a new EMT regulator. Both isoforms of E2-2 (E2-2A and \nE2-2B) induce a full EMT when overexpressed in MDCK cells but without affecting \nthe tumorigenic properties of parental cells, in contrast to other EMT inducers, \nsuch as Snail1 or class I bHLH E47. E-cadherin repression mediated by E2-2 is \nindirect and independent of proximal E-boxes of the promoter. Knockdown studies \nindicate that E2-2 expression is dispensable for maintenance of the EMT driven \nby Snail1 and E47. Comparative gene-profiling analysis reveals that E2-2 factors \ninduce similar, yet distinct, genetic programs to that induced by E47 in MDCK \ncells. These results, together with the embryonic expression pattern of Tcf4 and \nE2A (which encodes E12/E47), support a distinct role for E2-2 and suggest an \ninteresting interplay between E-cadherin repressors in the regulation of \nphysiological and pathological EMT processes.",
"AIM: To characterise expression of known E-cadherin repressors; Snail, Slug and \nTwist in the development of esophageal adenocarcinoma.\nMETHODS: E-cadherin, Slug, Snail and Twist mRNA expression in Barrett's \nmetaplasia and esophageal adenocarcinoma specimens was examined by real-time \nreverse transcription-polymerase chain reaction (RT-PCR). Semi-quantitative \nimmunohistochemistry was used to examine cellular localisation and protein \nlevels. The effect of Slug on epithelial mesenchymal transition (EMT) markers \nwas examined by transfection of Slug into an adenocarcinoma line OE33.\nRESULTS: Cellular localisation of Slug in Barrett's metaplasia was largely \ncytoplasmic whilst in adenocarcinoma it was nuclear. Semi-quantitative analysis \nindicated that Slug was more abundant in adenocarcinoma compared to matched \nBarrett's metaplastic specimens. Snail and Twist were expressed in \nadenocarcinoma but were cytoplasmic in location and not induced compared to \nBarrett's mucosa. These observations were supported by mRNA studies where only \nSlug mRNA was shown to be over-expressed in adenocarcinoma and inversely \ncorrelated to E-cadherin expression. Overexpression of Slug in OE33 mediated \nE-cadherin repression and induced the mesenchymal markers vimentin and \nfibronectin.\nCONCLUSION: Progression to adenocarcinoma is associated with increased Slug \nexpression and this may represent a mechanism of E-cadherin silencing.",
"What's known on the subject? and What does the study add? Epithelial-mesenchymal \ntransition (EMT) is involved in tumor progression where the underlying cellular \nchanges associated with EMT have been identified in in vitro models and \nconfirmed in a limited number of in vivo studies. ZEB1, which targets E-cadherin \nrepression, is a transcriptional regulator that has been implicated in EMT, and \nis associated with uterine and colorectal cancers. Regulation of ZEB1 expression \nhas been shown to involve different microRNAs (miRNAs), identifying a potential \nrole for miRNA in EMT. In the present study we have identified novel expression \nof ZEB1 in bladder tumours and shown a role for ZEB1 in enhanced migration and \ninvasion potential in in vitro assays. Confirmation of ZEB1 expression in \nbladder tumours was shown in tissue microarrays (TMAs).\nOBJECTIVE: To evaluate ZEB1 expression in bladder tumorigenesis and define a \npossible role for this transcription factor in urothelial carcinomas of the \nbladder (UCBs).\nMATERIALS AND METHODS: Five hundred and fifty-eight samples were assembled in 10 \ntissue microarrays (TMAs; 263 non-muscle-invasive Ta/T1/Tis, 295 muscle-invasive \nT2-T4). All tumours were transitional cell carcinomas (TCCs) and processed for \nimmunohistochemistry to assess nuclear ZEB1 expression. Expression levels of \nZEB1 were modulated in bladder carcinoma cell lines CUBIII or UM-UC-3 after \nforced expression or shRNA knockdown, respectively. Protein expression levels \nwere determined using western blot analysis and transfectants were assessed for \nmigration and invasion potential in standard in vitro assays.\nRESULTS: Nuclear ZEB1 expression was recorded in 22.8% of non-muscle-invasive \nUCBs and 21.7% of muscle-invasive UCBs, including 24.1% grade I/II and 21.1% \ngrade III tumours, and absent in normal bladder mucosa. No significant \ncorrelation was observed for tumour stage and grade, nodal involvement, vascular \ninvasion, metastasis and overall or cancer-specific survival. The introduction \nor knockdown of ZEB1 expression in bladder carcinoma cell lines showed enhanced \nor reduced migration and invasive potential, respectively. Changes in ZEB1 \nexpression were accompanied by altered microRNA (miRNA) expression underlying \nevents linked to epithelial-mesenchymal transition (EMT).\nCONCLUSION: The results in the present study showed novel expression of ZEB1 in \nbladder cancer in the absence of a link to clinical variables of change, \nincluding metastasis and survival. However, in vitro assays showed enhanced or \nreduced migration and invasion after the introduction or reduction of ZEB1, \nrespectively, in transfected bladder cell lines. Modulation in expression of \nZEB1 was closely linked to changes in the miR-200 family along with alternative \nknown prognostic indicators of bladder tumour progression."
] | ['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0001837', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015820', 'http://www.uniprot.org/uniprot/CADH1_HUMAN', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D058750', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014157', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0060231'] |
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] | train | Which transcription factors are known as the four (4) "Yamanaka factors" that have been used to create induced pluripotent stem cells (iPSCs)? | list | Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM). In particular, the mechanisms how the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) directly drive reprogramming and which additional components are involved are still not yet understood. | ['Oct4', 'Sox2', 'Klf4', 'c-Myc'] | [
"Cellular reprogramming consists of the conversion of differentiated cells into \npluripotent cells; the so-called induced Pluripotent Stem Cells. iPSC are \namenable to in vitro manipulation and, in theory, direct production of any \ndifferentiated cell type. Furthermore, iPSC can be obtained from sick \nindividuals and subsequently used for disease modeling, drug discovery and \nregenerative treatments. iPSC production was first achieved by transducing, with \nthe use of retroviral vectors, four specific transcription factors: Oct4, Klf4, \nSox2 and c-Myc (OKSM), into primary cells in culture Takahashi and Yamanaka, \n(Cell 126(4):663-676, 2006). Many alternative protocols have since been \nproposed: repeated transfections of expression plasmids containing the four \npluripotency-associated genes Okita et al. (Science 322(5903):949-953, 2008), \nlentiviral delivery of the four factors Sommer et al. (Stem Cells 27(3):543-549, \n2009), Sendai virus delivery Fusaki et al. (Proceedings of the Japan Academy. \nSeries B, Physical and Biological Sciences 85(8):348-362, 2009), removal of the \nreprogramming vectors by 'piggyBac' transposition Woltjen et al. (Nature \n458(7239):766-770, 2009); Kaji et al. (Nature 458(7239):771-775, 2009), \nCre-recombinase excisable viruses Soldner et al. (Cell 136(5):964-977, 2009), \nepisomal vectors Yu et al. (Science 324(5928):797-801, 2009), cell-penetrating \nreprogramming proteins Zhou et al. (Stem Cells 4(5):381-384, 2009), mammalian \nartificial chromosomes Hiratsuka et al. (PLoS One 6(10):e25961, 2011) \nsynthetically modified mRNAs Warren et al. (Scientific Reports 2:657, 2012), \nmiRNA Anokye-Danso et al. (Cell Stem Cell 8(4):376-388, 2009); however, although \nsome of these methods are commercially available, in general they still need to \nattain the reproducibility and reprogramming efficiency required for routine \napplications Mochiduki and Okita (Biotechnol Journal 7(6):789-797, 2012). Herein \nwe explain, in four detailed protocols, the isolation of mouse and human somatic \ncells and their reprogramming into iPSC. All-encompassing instructions, not \npreviously published in a single document, are provided for mouse and human iPSC \ncolony isolation and derivation. Although mouse and human iPSC share \nsimilarities in the cellular reprogramming process and culture, both cell types \nneed to be handled differently.",
"Induced pluripotent stem cells (iPSCs) are created by the reprogramming of \nsomatic cells via overexpression of certain transcription factors, such as the \noriginally described Yamanaka factors: Oct4, Sox2, Klf4, and c-Myc (OSKM). Here \nwe discuss recent advancements in iPSC reprogramming and introduce mathematical \napproaches to help map the landscape between cell states during reprogramming. \nOur modelization indicates that OSKM expression diminishes and/or changes \npotential barriers between cell states and that epigenetic remodeling facilitate \nthese transitions. From a practical perspective, the modeling approaches \noutlined here allow us to predict the time necessary to create a given number of \niPSC colonies or the number of reprogrammed cells generated in a given time. \nAdditional investigations will help to further refine modeling strategies, \nrendering them applicable toward the study of the development and stability of \ncancer cells or even other reprogramming processes such as lineage conversion. \nUltimately, a quantitative understanding of cell state transitions might \nfacilitate the establishment of regenerative medicine strategies and enhance the \ntranslation of reprogramming technologies into the clinic.",
"Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by \nthe application of Yamanaka factors (OSKM), but the mechanisms underlying this \nreprogramming remain poorly understood. Here, we report that Sox2 directly \nregulates endogenous microRNA-29b (miR-29b) expression during iPSC generation \nand that miR-29b expression is required for OSKM- and OSK-mediated \nreprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo \ntargets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated \nwith miR-29b expression during reprogramming. Moreover, the effect of miR-29b on \nreprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further \nexperiments indicate that miR-29b-DNMT signaling is significantly involved in \nthe regulation of DNA methylation-related reprogramming events, such as \nmesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. \nThus, our studies not only reveal that miR-29b is a novel mediator of \nreprogramming factor Sox2 but also provide evidence for a multistep mechanism in \nwhich Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA \nmethylation-related events during reprogramming.",
"Human induced pluripotent stem cells (iPSCs) have become an intriguing approach \nfor neurological disease modeling, because neural lineage-specific cell types \nthat retain the donors' complex genetics can be established in vitro. The \nstatistical power of these iPSC-based models, however, is dependent on accurate \ndiagnoses of the somatic cell donors; unfortunately, many neurodegenerative \ndiseases are commonly misdiagnosed in live human subjects. Postmortem \nhistopathological examination of a donor's brain, combined with premortem \nclinical criteria, is often the most robust approach to correctly classify an \nindividual as a disease-specific case or unaffected control. In this study, we \ndescribe iPSCs generated from a skin biopsy collected postmortem during the \nrapid autopsy of a 75-year-old male, whole body donor, defined as an unaffected \nneurological control by both clinical and histopathological criteria. These \niPSCs were established in a feeder-free system by lentiviral transduction of the \nYamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. Selected iPSC clones expressed \nboth nuclear and surface antigens recognized as pluripotency markers of human \nembryonic stem cells (hESCs) and were able to differentiate in vitro into \nneurons and glia. Statistical analysis also demonstrated that fibroblast \nproliferation was significantly affected by biopsy site, but not donor age \n(within an elderly cohort). These results provide evidence that autopsy \ndonor-derived fibroblasts can be successfully reprogrammed into iPSCs, and may \nprovide an advantageous approach for generating iPSC-based neurological disease \nmodels.",
"CytoTune™-iPS Reprogramming System uses vectors based on replication in \ncompetent Sendai virus (SeV) to safely and effectively deliver and express key \ngenetic factors necessary for reprogramming somatic cells into iPSCs. In \ncontrast to many available protocols, which rely on viral vectors that integrate \ninto the genome of the host cell, the CytoTune™ Reprogramming System uses \nvectors that are non-integrating and remain in the cytoplasm (i.e., they are \nzero-footprint). In addition, the host cell can be cleared of the vectors and \nreprogramming factor genes by exploiting the cytoplasmic nature of SeV and the \nfunctional temperature sensitivity mutations introduced into the key viral \nproteins. The CytoTune™-iPS Reprogramming Kit contains four SeV-based \nreprogramming vectors, each capable of expressing one of the four Yamanaka \nfactors (i.e., Oct4, Sox2, Klf4, and c-Myc) and are optimized for generating \niPSCs from human somatic cells. The reprogramming vectors in this kit have been \nengineered to increase biological and environmental safety.",
"Delivery of the transcription factors Oct4, Klf4, Sox2 and c-Myc via integrating \nviral vectors has been widely employed to generate induced pluripotent stem cell \n(iPSC) lines from both normal and disease-specific somatic tissues, providing an \ninvaluable resource for medical research and drug development. Residual \nreprogramming transgene expression from integrated viruses nevertheless alters \nthe biological properties of iPSCs and has been associated with a reduced \ndevelopmental competence both in vivo and in vitro. We performed transcriptional \nprofiling of mouse iPSC lines before and after excision of a polycistronic \nlentiviral reprogramming vector to systematically define the overall impact of \npersistent transgene expression on the molecular features of iPSCs. We \ndemonstrate that residual expression of the Yamanaka factors prevents iPSCs from \nacquiring the transcriptional program exhibited by embryonic stem cells (ESCs) \nand that the expression profiles of iPSCs generated with and without c-Myc are \nindistinguishable. After vector excision, we find 36% of iPSC clones show normal \nmethylation of the Gtl2 region, an imprinted locus that marks ESC-equivalent \niPSC lines. Furthermore, we show that the reprogramming factor Klf4 binds to the \npromoter region of Gtl2. Regardless of Gtl2 methylation status, we find similar \nendodermal and hepatocyte differentiation potential comparing syngeneic Gtl2(ON) \nvs Gtl2(OFF) iPSC clones. Our findings provide new insights into the \nreprogramming process and emphasize the importance of generating iPSCs free of \nany residual transgene expression.",
"The recently established reprogramming of somatic cells into induced pluripotent \nstem cells (iPSCs) by Takahashi and Yamanaka represents a valuable tool for \nfuture therapeutic applications. To date, the mechanisms underlying this process \nare still largely unknown. In particular, the mechanisms how the Yamanaka \nfactors (Oct4, Sox2, Klf4, and c-Myc) directly drive reprogramming and which \nadditional components are involved are still not yet understood. In this study, \nwe aimed at analyzing the role of ADP-ribosyltransferase diphtheria toxin-like \none (Artd1; formerly called poly(ADP-ribose) polymerase 1 [Parp1]) during \nreprogramming. We found that poly(ADP-ribosylation) (PARylation) of the \nreprogramming factor Sox2 by Artd1 plays an important role during the first days \nupon transduction with the reprogramming factors. A process that happens before \nArtd1 in conjunction with 10-11 translocation-2 (Tet2) mediates the histone \nmodifications necessary for the establishment of an activated chromatin state at \npluripotency loci (e.g., Nanog and Essrb) [Nature 2012;488:652-655]. Wild-type \n(WT) fibroblasts treated with an Artd1 inhibitor as well as fibroblasts \ndeficient for Artd1 (Artd1-/-) show strongly decreased reprogramming capacity. \nOur data indicate that Artd1-mediated PARylation of Sox2 favors its binding to \nthe fibroblast growth factor 4 (Fgf4) enhancer, thereby activating Fgf4 \nexpression. The importance of Fgf4 during the first 4 days upon initiation of \nreprogramming was also highlighted by the observation that exogenous addition of \nFgf4 was sufficient to restore the reprogramming capacity of Artd1-/- fibroblast \nto WT levels. In conclusion, our data clearly show that the interaction between \nArtd1 and Sox2 is crucial for the first steps of the reprogramming process and \nthat early expression of Fgf4 (day 2 to day 4) is an essential component for the \nsuccessful generation of iPSCs.",
"Through the ectopic expression of four transcription factors, Oct4, Klf4, Sox2 \nand cMyc, human somatic cells can be converted to a pluripotent state, \ngenerating so-called induced pluripotent stem cells (iPSCs)(1-4). \nPatient-specific iPSCs lack the ethical concerns that surround embryonic stem \ncells (ESCs) and would bypass possible immune rejection. Thus, iPSCs have \nattracted considerable attention for disease modeling studies, the screening of \npharmacological compounds, and regenerative therapies(5). We have shown the \ngeneration of transgene-free human iPSCs from patients with different lung \ndiseases using a single excisable polycistronic lentiviral Stem Cell Cassette \n(STEMCCA) encoding the Yamanaka factors(6). These iPSC lines were generated from \nskin fibroblasts, the most common cell type used for reprogramming. Normally, \nobtaining fibroblasts requires a skin punch biopsy followed by expansion of the \ncells in culture for a few passages. Importantly, a number of groups have \nreported the reprogramming of human peripheral blood cells into iPSCs(7-9). In \none study, a Tet inducible version of the STEMCCA vector was employed(9), which \nrequired the blood cells to be simultaneously infected with a constitutively \nactive lentivirus encoding the reverse tetracycline transactivator. In contrast \nto fibroblasts, peripheral blood cells can be collected via minimally invasive \nprocedures, greatly reducing the discomfort and distress of the patient. A \nsimple and effective protocol for reprogramming blood cells using a constitutive \nsingle excisable vector may accelerate the application of iPSC technology by \nmaking it accessible to a broader research community. Furthermore, reprogramming \nof peripheral blood cells allows for the generation of iPSCs from individuals in \nwhich skin biopsies should be avoided (i.e. aberrant scarring) or due to \npre-existing disease conditions preventing access to punch biopsies. Here we \ndemonstrate a protocol for the generation of human iPSCs from peripheral blood \nmononuclear cells (PBMCs) using a single floxed-excisable lentiviral vector \nconstitutively expressing the 4 factors. Freshly collected or thawed PBMCs are \nexpanded for 9 days as described(10,11) in medium containing ascorbic acid, SCF, \nIGF-1, IL-3 and EPO before being transduced with the STEMCCA lentivirus. Cells \nare then plated onto MEFs and ESC-like colonies can be visualized two weeks \nafter infection. Finally, selected clones are expanded and tested for the \nexpression of the pluripotency markers SSEA-4, Tra-1-60 and Tra-1-81. This \nprotocol is simple, robust and highly consistent, providing a reliable \nmethodology for the generation of human iPSCs from readily accessible 4 ml of \nblood.",
"BACKGROUND: Although recent studies have identified genes expressed in human \nembryonic stem cells (hESCs) that induce pluripotency, the molecular \nunderpinnings of normal stem cell function remain poorly understood. The high \nmobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly \ndifferentiated, stem-like cancers; however, its role in these settings has been \nunclear.\nMETHODS/PRINCIPAL FINDINGS: We show that HMGA1 is highly expressed in fully \nreprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in \nfibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and \nparallels that of other pluripotency factors. Conversely, forced expression of \nHMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances \ncellular reprogramming of somatic cells to iPSCs together with the Yamanaka \nfactors (OCT4, SOX2, KLF4, cMYC - OSKM). HMGA1 increases the number and size of \niPSC colonies compared to OSKM controls. Surprisingly, there was normal \ndifferentiation in vitro and benign teratoma formation in vivo of the \nHMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the \nexpression of pluripotency genes, including SOX2, LIN28, and cMYC, while \nknockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin \nimmunoprecipitation shows that HMGA1 binds to the promoters of these \npluripotency genes in vivo. In addition, interfering with HMGA1 function using a \nshort hairpin RNA or a dominant-negative construct blocks cellular reprogramming \nto a pluripotent state.\nCONCLUSIONS: Our findings demonstrate for the first time that HMGA1 enhances \ncellular reprogramming from a somatic cell to a fully pluripotent stem cell. \nThese findings identify a novel role for HMGA1 as a key regulator of the stem \ncell state by inducing transcriptional networks that drive pluripotency. \nAlthough further studies are needed, these HMGA1 pathways could be exploited in \nregenerative medicine or as novel therapeutic targets for poorly differentiated, \nstem-like cancers.",
"The ability to efficiently generate integration-free induced pluripotent stem \ncells (iPSCs) from the most readily available source-peripheral blood-has the \npotential to expedite the advances of iPSC-based therapies. We have successfully \ngenerated integration-free iPSCs from cord blood (CB) CD34(+) cells with \nimproved oriP/EBNA1-based episomal vectors (EV) using a strong spleen focus \nforming virus (SFFV) long terminal repeat (LTR) promoter. Here we show that \nYamanaka factors (OCT4, SOX2, MYC, and KLF4)-expressing EV can also reprogram \nadult peripheral blood mononuclear cells (PBMNCs) into pluripotency, yet at a \nvery low efficiency. We found that inclusion of BCL-XL increases the \nreprogramming efficiency by approximately 10-fold. Furthermore, culture of \nCD3(-)/CD19(-) cells or T/B cell-depleted MNCs for 4-6 days led to the \ngeneration of 20-30 iPSC colonies from 1 ml PB, an efficiency that is \nsubstantially higher than previously reported. PB iPSCs express pluripotency \nmarkers, form teratomas, and can be induced to differentiate in vitro into \nmesenchymal stem cells, cardiomyocytes, and hepatocytes. Used together, our \noptimized factor combination and reprogramming strategy lead to efficient \ngeneration of integration-free iPSCs from adult PB. This discovery has potential \napplications in iPSC banking, disease modeling and regenerative medicine."
] | ['http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D057026', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D039904'] |
553656c4bc4f83e828000009 | [
9213191,
2162733,
7571088,
17009618,
1333942,
23674776,
7591257,
3004699
] | train | Which translocation is harbored in the Askin tumor cells? | factoid | The Askin tumor is a primitive malignant small-cell tumor of the chest wall mostly seen among children and adolescents. It is closely related to Ewing's sarcoma of the same location, with both tumors harboring reciprocal translocation t(11;22) (q24;q12). | 1 | [
"A rare case of peripheral primitive neuroectodermal tumor (PNET) is reported. A \n68-year-old woman complaining of lumbago was admitted to our hospital. Diagnosis \nwas made based on pathological findings characterized by Homer Wright-type \nrosettes. Ultrastructural examination showed the presence of neurosecretory \ngranules and short cytoplasmic processes, which were highly suggestive of neural \ndifferentiation. Chromosomal analysis of the neoplastic cells revealed \ntranslocation (11;22)(q24;q12), which is often found in Ewing's sarcoma and \nAskin tumor. These results strengthen the hypothesis of a common histogenesis \nfor these small round cell tumors, and suggest common oncogenesis for these \nneoplasms.",
"A patient previously reported to have Ewing's sarcoma showed a t(11;22) \n(q23;q11) and spontaneous expression of fra(11)(q23) [1]. Subsequent review of \npathologic specimen indicated, however, that it was an Askin's tumor. Reciprocal \ntranslocations of chromosomes 11 and 22 are the most common cytogenetic \nabnormalities in Ewing's sarcoma and the related Askin's tumor. After radiation \ntherapy of a residual metastatic brain lesion, subsequent studies of the \nrecurrent brain tumor indicated the presence of the original translocations as \nwell as five new reciprocal translocations and two deleted segments (9p-, 10p-). \nThe new chromosome abnormalities were consistently found, indicating that \nprogression of the tumor was clonal. The newly observed clonal aberrations were \nconsidered secondary in nature. A relationship between craniocerebral \nirradiation and development of brain tumors has been reported in several \nstudies, but the mechanism for tumor induction has not yet been elucidated. It \nis important that the role of radiation therapy in the evolutionary process of \nchromosomal changes be studied in a large group of similar cases.",
"Malignant small cell tumor of the thoracopulmonary region (MSCT) was first \ndescribed in 1979 and has been referred to as the Askin tumor. This malignant \nneoplasm is a member of the peripheral primitive neuroectodermal tumor (PPNET) \nfamily and typically involves the periosteum, soft tissue, and extrapulmonary \ntissue of the thoracic wall. MSCT may also involve the lung parenchyma by local \nextension or may arise de novo in peripheral lung tissue. Local recurrence, \nabdominal involvement by tumor extravasation across the diaphragm, and skeletal \nmetastatic disease are relatively common. However, metastasis to the head and \nneck region and in particular to the oral cavity is extremely rare. We present a \nrecurrent intrapulmonary MSCT with metastasis to the oral cavity in an \nadolescent Hispanic boy, and review the literature regarding this member of the \nPPNET family. Differentiation from neuroblastoma may be made based on \nimmunoreactivity for beta 2 microglobulin and HBA71 and lack of immunoreactivity \nfor chromogranin in PPNET and MSCT. Ultrastructural features commonly seen in \nMSCT and PPNET are round to ovoid tumor cells with occasional cytoplasmic \nprocesses with relatively few pleomorphic dense core granules. These tumors lack \nthe gangliocytic and Schwann cell differentiation that is characteristic of \nneuroblastoma. MSCT and PPNET have a common reciprocal cytogenetic translocation \n[t(11;22)q(24;q12)], which is shared with Ewing's sarcoma. Prognosis in MSCT is \nquite dismal, with a 2-year survival of 38% and a 6-year survival of only 14%.",
"Ewing tumor family consists of Ewing tumor of bone, extraosseous Ewing tumor, \nprimitive neurectodermal tumor and Askin tumor. All of them share genetic \nabnormality, reciprocal translocation (11; 22) (q24; q12), and originate from \nthe same primordial stem cell. Ewing tumor is the most common form, found in 60% \nof cases. It is the second primary malignant bone tumor. Localized lesion is \nfound in nearly 80% and metastatic disease in 20% of cases. Patients present \nmostly due to pain and palpable tumefaction, and pathological fracture as the \ninitial problem develops in long bones. Ewing tumor can develop in virtually any \nbone of the body and in extraosseous localizations as well, while localization \nin the extremities occurs in 50% of patients. Head or neck localizations are \nextremely rare. Paraspinal, retroperitoneal or deep pelvic tumor localization is \nmanifested by back pain. Systemic symptoms are also present, commonly fever or \nweight loss, which often indicates the presence of metastatic disease with \npredominant invasion of lung, bone and bone marrow. Multimodal chemotherapy with \nlocal radiation and/or surgical resection is the best way of modern treatment. \nDistal parts of extremities and axial skeleton are good prognostic features, \nwhile proximal parts, pelvic girdle, metastatic disease and low index of \npostchemotherapeutic necrosis are associated with poor outcome.",
"The Askin tumor, a primitive malignant small-cell tumor of the chest wall, is \nmostly seen among children and adolescents. It is closely related to Ewing's \nsarcoma of the same location, both tumors showing a chromosomal translocation \nt(11;22). Its origin from neuroectodermal cells is deducted from several \nultrastructural details and from the expression of specific markers like NSE. \nPain and deformation of the chest wall are the cardinal clinical signs of the \ntumor. Chest X-rays will frequently show destruction of ribs and pleural \neffusions. Effective therapy consists of radical surgery, local radiation and \nadjuvant chemotherapy. This multimodal concept allows minority of patients to \nremain disease-free but the overall outcome is rather unfortunate.",
"The Ewing sarcoma family of tumors includes osseous Ewing sarcoma, extraskeletal \nEwing sarcoma, primitive neuroectodermal tumor, and Askin tumor. They share a \nkaryotype abnormality with translocation involving chromosomes 11 and 22. \nHistologically, these lesions demonstrate crowded sheets of small round blue \ncells. Imaging features of osseous Ewing sarcoma often suggest the diagnosis, \nwith aggressive long-bone destruction in the metadiaphysis of an adolescent or \nyoung adult and an associated soft-tissue mass. Focal areas of cortical \ndestruction are frequent, allowing continuity between the intraosseous and \nextraosseous components. This continuity is also commonly seen as subtle \nchannels extending through the cortex at computed tomography or magnetic \nresonance (MR) imaging, a finding that reflects the underlying pathologic \nappearance. Extraskeletal Ewing sarcoma commonly demonstrates a nonspecific \nradiologic appearance of a large soft-tissue mass affecting the paraspinal \nregion or lower extremity. Askin tumor represents extraskeletal Ewing sarcoma \ninvolving the chest wall. Imaging typically reveals a large pleural-based mass \nand associated pleural effusion. Treatment of these tumors is usually a \ncombination of neoadjuvant chemotherapy followed by surgical resection, which \nmay be supplemented with radiation therapy. Imaging, particularly MR, is also \nvital to evaluate response to neoadjuvant therapy, direct surgical resection, \nand detect local recurrence or metastatic disease.",
"The t(11;22)(q24;q12) and t(21;22)(q22;q12) are specific chromosomal \ntranslocations found in the Ewing family of tumors including ES, PNET and Askin \ntumors. In these translocations, the amino-terminal portion of the EWS gene \nlocated in 22q12 fuses to the carboxyl-terminal portion of the FLI-1 gene \nlocated in 11q24 or the ERG gene located in 21q22, which belong to the ets \noncogene superfamily of transcription activators. We investigated the chimeric \nmRNAs of 15 ESs (7 cell lines and 8 tumor samples) and 7 PNETs (3 cell lines and \n4 tumor samples) using the RT-PCR method and sequencing. We detected 2 types of \nEWS-ERG chimeric mRNA in 2 ES cell lines and 1 PNET tumor sample in addition to \n4 types of EWS-FLI-1 chimeric mRNA in 11 ESs (4 cell lines and 7 tumor samples) \nand 4 PNETs (2 cell lines and 2 tumor samples). There seemed to be no \nassociation between the type of chimeric mRNA and clinical features such as sex, \nage, primary site and histopathology of the patients. All of the chimeric mRNAs \nare generated from in-frame junctions and are thought to encode fusion proteins \nthat may be the molecular mechanism involved in the Ewing family of tumors.",
"Small, round, blue-cell tumors (SRCT), including rhabdomyosarcoma, Ewing's \nsarcoma of bone and soft tissue, mesenchymal chondrosarcoma, small cell \nosteosarcoma, hemangiopericytoma, neuroblastoma, peripheral neurectodermal tumor \n(peripheral neuroepithelioma of bone and soft tissue), and the malignant small \ncell tumor of the thoracopulmonary region described by Askin (Askin's tumor), \nare often difficult to distinguish by light microscopy. We have evaluated the \ncytogenetics of these tumors by studying 24 tumor explants in short-term culture \nand 22 tumor cell lines. In Ewing's sarcoma (a tumor of unknown histogenesis), \nand in peripheral neuroepithelioma and Askin's tumor (tumors with evidence of \nneural origin), we have observed an indistinguishable t(11;22) translocation."
] | ['http://www.disease-ontology.org/api/metadata/DOID:0050608'] |
552faababc4f83e828000005 | [
16864960,
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] | train | Which translocation is the hallmark of Ewing sarcoma? | factoid | Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant neoplasms that most often affect children and young adults in the first 2 decades of life. The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24; 12), is detected in 95% of ES patients | 1 | [
"Ewing's sarcoma (ES) is a highly malignant tumor composed of uniform small round \ncells. Recently, a single biologic entity, Ewing's sarcoma family of tumors \n(ESFT) has been accepted. The entity includes ES, extraskeletal Ewing's sarcoma \n(EES) and primitive neuroectodermal tumor (PNET). ESFT cells have \nimmunoreactivity for CD99, an antigen determined by the MIC2 gene. Most ESFT has \nthe (11;22) (q24;q12) translocation. The translocation results in the fusion of \nthe EWS gene with the transcription factor gene FLI1 which has been considered a \nhallmark of ESFT. We present an extremely unusual case with ESFT in a spinal \nnerve root mimicking a neurogenic dumbbell tumor. A male aged 20 years noticed \npain in his right buttock. Magnetic resonance imaging (MRI) revealed a mass in \nthe right L5/S intervertebral foramen and the lesions in the sacrum. Surgery was \nperformed with a presumptive diagnosis of a nerve sheath tumor. At surgery, the \ntumor was located in the right L5 nerve root sleeve. The sacral lesions were \nobserved closely. At one month after surgery, radiologically multiple lesions \nwere detected in the pelvic bones. Microscopically the lesions from the root and \nilium were composed of small round cells immunoreactive for CD99. Reverse \ntranscription-polymerase chain reaction detected transcripts resulting from the \nfusion of the EWS gene with FLI1 genes in the iliac lesion. Immunoreactivity for \nCD99 and detection of the EWS-FLI1 hybrid transcripts are important for the \ncorrect diagnosis of ESFT arising in an unusual location.",
"Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone \nsarcomas occurring in young people. Rare-disease clinical trials can require \nglobal collaborations and many years. In vivo models that as accurately as \npossible reflect the clinical disease are helpful in selecting therapeutics with \nthe most promise of positive clinical impact. Human Ewing/PNET sarcoma cell \nlines developed over the past 45 years are described. Several of these have \nundergone genetic analysis and have been confirmed to be those of Ewing/PNET \nsarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in \nunderstanding the biology of this disease in the mouse. The chromosomal \ntranslocation producing the EWS/FLI1 fusion transcript characterizes clinical \nEwing sarcoma. Cell lines that express this genetic profile are confirmed to be \nthose of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a \nxenograft in immunodeficient mice. The A673 model has been used to study Ewing \nsarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma \nclinical specimens express the cell surface protein endosialin. Several Ewing \nsarcoma cell lines, including the A673 line, also express cell surface \nendosialin when grown as subcutaneous tumor nodules and as disseminated disease; \nthus the A673 is a useful model for the study of endosialin biology and \nendosialin-directed therapies. With the advent of tools that allow \ncharacterization of clinical disease to facilitate optimal treatment, it becomes \nimperative, especially for rare tumors, to develop preclinical models reflecting \ndisease subsets. Ewing PNET sarcomas are a rare disease where models are \navailable.",
"Chromosomal translocation that results in fusion of the genes encoding \nRNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is \npathognomonic for Ewing sarcoma. EWS-FLI1 alters gene expression through \nmechanisms that are not completely understood. We performed RNA sequencing \n(RNAseq) analysis on primary pediatric human mesenchymal progenitor cells \n(pMPCs) expressing EWS-FLI1 in order to identify gene targets of this \noncoprotein. We determined that long noncoding RNA-277 (Ewing sarcoma-associated \ntranscript 1 [EWSAT1]) is upregulated by EWS-FLI1 in pMPCs. Inhibition of EWSAT1 \nexpression diminished the ability of Ewing sarcoma cell lines to proliferate and \nform colonies in soft agar, whereas EWSAT1 inhibition had no effect on other \ncell types tested. Expression of EWS-FLI1 and EWSAT1 repressed gene expression, \nand a substantial fraction of targets that were repressed by EWS-FLI1 were also \nrepressed by EWSAT1. Analysis of RNAseq data from primary human Ewing sarcoma \nfurther supported a role for EWSAT1 in mediating gene repression. We identified \nheterogeneous nuclear ribonucleoprotein (HNRNPK) as an RNA-binding protein that \ninteracts with EWSAT1 and found a marked overlap in HNRNPK-repressed genes and \nthose repressed by EWS-FLI1 and EWSAT1, suggesting that HNRNPK participates in \nEWSAT1-mediated gene repression. Together, our data reveal that EWSAT1 is a \ndownstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma \nvia the repression of target genes.",
"BACKGROUND: Chromosomal translocations generating oncogenic transcription \nfactors are the hallmark of a variety of tumors, including many sarcomas. Ewing \nsarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) \ntranslocation that generates the Ewing sarcoma breakpoint region 1 and Friend \nleukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible \nfor the highly malignant phenotype of this tumor. Although continued expression \nof EWS-FLI1 is believed to be critical for ESFT cell survival, a clinically \neffective small-molecule inhibitor remains elusive likely because EWS-FLI1 is a \ntranscription factor and therefore widely felt to be \"undruggable.\"\nMETHODS: We developed a high-throughput screen to evaluate more than 50 000 \ncompounds for inhibition of EWS-FLI1 activity in TC32 ESFT cells. We used a TC32 \ncell-based luciferase reporter screen using the EWS-FLI1 downstream target NR0B1 \npromoter and a gene signature secondary screen to sort and prioritize the \ncompounds. We characterized the lead compound, mithramycin, based on its ability \nto inhibit EWS-FLI1 activity in vitro using microarray expression profiling, \nquantitative reverse transcription-polymerase chain reaction, and immunoblot \nanalysis, and in vivo using immunohistochemistry. We studied the impact of this \ninhibition on cell viability in vitro and on tumor growth in ESFT xenograft \nmodels in vivo (n = 15-20 mice per group). All statistical tests were two-sided.\nRESULTS: Mithramycin inhibited expression of EWS-FLI1 downstream targets at the \nmRNA and protein levels and decreased the growth of ESFT cells at half maximal \ninhibitory concentrations between 10 (95% confidence interval [CI] = 8 to 13 nM) \nand 15 nM (95% CI = 13 to 19 nM). Mithramycin suppressed the growth of two \ndifferent ESFT xenograft tumors and prolonged the survival of ESFT \nxenograft-bearing mice by causing a decrease in mean tumor volume. For example, \nin the TC32 xenograft model, on day 15 of treatment, the mean tumor volume for \nthe mithramycin-treated mice was approximately 3% of the tumor volume observed \nin the control mice (mithramycin vs control: 69 vs 2388 mm(3), difference = 2319 \nmm(3), 95% CI = 1766 to 2872 mm(3), P < .001).\nCONCLUSION: Mithramycin inhibits EWS-FLI1 activity and demonstrates ESFT \nantitumor activity both in vitro and in vivo.",
"Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant \nneoplasms that most often affect children and young adults in the first 2 \ndecades of life. The EWS/Fli-1 fusion gene, a product of the translocation \nt(11;22) (q24; 12), is detected in 95% of ES patients. Recently, it was \nvalidated that cells emit a heterogeneous mixture of vesicular, organelle-like \nstructures (microvesicles, MVs) into their surroundings including blood and body \nfluids, and that these MVs contain a selected set of tumor-related proteins and \nhigh levels of mRNAs and miRNAs. In this present study, we detected the Ewing \nsarcoma-specific EWS/Fli-1 mRNA in MVs from the culture medium of ES cell lines \ncarrying t(11;22) (q24; 12). Also, we detected this fusion gene in approximately \n40% of the blood samples from mice inoculated with xenografts of TC135 or A673 \ncells. These findings indicate the EWS/Fli-1 mRNA in MVs might be a new \nnon-invasive diagnostic marker for specific cases of Ewing sarcoma.",
"The chromosomal translocation t(11;22)(q24;q12) yields the EWS-Fli1 fusion gene, \nwhich contributes to the development of Ewing Family Tumors (EFTs). Previous \nstudies have shown the ability of EWS-Fli1 chimeric protein to silence p53 \nactivity. Here we demonstrate that the introduction of EWS-Fli1 significantly \ninhibited p300-mediated acetylation of p53 at Lys-382 and depletion of EWS-Fli1 \nprotein by small interfering RNAs (siRNA) in EFTs cells facilitated it in \nresponse to DNA damage. Furthermore, the deacetylation of p53 by EWS-Fli1 \nsuppressed its transcriptional activity and enhanced mdm2-mediated p53 \ndegradation. On the other hand, immunoprecipitation study shows that N-terminal \nregion of EWS-Fli1 associated with histone deacetylase 1 (HDAC1) to forms a \ncomplex with p53. Knockdown of HDAC1, but not HDAC2 or HDAC3 protein restored \nthe expression of p53 Lys-382 in EFTs cells. Overexpression of HDAC1 also \nsignificantly inhibited p53 transcriptional activity. Pharmacologic inhibitor of \nHDAC, trichostatin A (TSA) promoted p53-p300 interaction and recruitment of p53 \nLys-382 to promoter regions of its target genes p21 and Puma, consequently \ninducing apoptosis and stabilizing the acetylation of p53 at Lys-382 together \nwith the upregulation of p21 and Puma, which were impaired in EFTs cells after \nthe knockdown of p53 expression. Our data indicate EWS-Fli1 might deacetylate \np53 to inhibit its transcriptional function and protein stability via the \nrecruitment of HDAC1. These results might elucidate a novel molecular mechanism \nabout the abrogation of p53 pathway by EWS-Fli1 in EFTs pathogenesis.",
"BACKGROUND: Ewing's sarcoma is a malignancy characterized by a specific 11:22 \nchromosomal translocation which generates a novel EWS-FLI1 fusion protein \nfunctioning as an aberrant transcription factor. In the present study, we have \nfurther characterized the junction region of the EWS-FLI1 fusion protein.\nMETHODS: In-silico model of EWS-FLI1 fusion protein was analysed for ligand \nbinding sites, and a putative region (amino acid (aa) 251-343 of the type 1 \nfusion protein) in the vicinity of the fusion junction was cloned and expressed \nusing bacterial expression. The recombinant protein was characterized by \nCircular Dichroism (CD). We then expressed aa 251-280 ectopically in Ewing's \nsarcoma cell-line and its effect on cell proliferation, tumorigenicity and \nexpression of EWS-FLI1 target genes were analysed.\nRESULTS: Our modelling analysis indicated that Junction region (aa 251-343) \nencompasses potential ligand biding sites in the EWS-FLI1 protein and when \nexpressed in bacteria was present as soluble form. Ectopically expressing this \nregion in Ewing's sarcoma cells inhibited tumorigenicity, and EWS-FLI1 target \ngenes indicating a dominant negative biological effect.\nCONCLUSIONS: Junction region can be exploited further as target for drug \ndevelopment in future to specifically target EWS-FLI1 in Ewing's Sarcoma.",
"Translocations involving ETS-transcription factors, most commonly leading to the \nEWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge \nof this driving molecular event, an effective therapeutic strategy is lacking. \nTo test potential treatment regimes, we established a novel Ewing sarcoma \nzebrafish engraftment model allowing time-effective, dynamic quantification of \nEwing sarcoma progression and tumour burden in vivo, applicable for screening of \nsingle and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 \nis commonly found to be wild-type, thus providing an attractive target for \ntreatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and \nTP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating \neffect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block \ntranscriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 \ntranscriptional activity reduced Ewing sarcoma tumour cell burden irrespective \nof TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to \nstabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma \ncell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved \ninhibition of proliferation and migration by combinatorial treatment was \nconfirmed in vivo by zebrafish engraftments. Mechanistically, both compounds \ntogether additively induced apoptosis of tumour cells in vivo by engaging \ndistinct pathways. We propose reactivation of the p53 pathway in combination \nwith complementary targeted therapy by EWSR1-FLI1 transcriptional activity \ndisruption as a valuable strategy against p53 wild-type Ewing sarcoma.",
"Primitive neuroectodermal tumors are in the Ewing's sarcoma family of tumors and \nare composed of small round cells. Because of their rare occurrence, optimal \ntherapy is challenging, particularly if they occur in the head and neck. \nDiagnosis is based on history, immunostaining with at least 2 neural markers, \nultrastructural examination, and evidence of an abnormal t(11;22)(q24;q12) \ntranslocation as the hallmark for the Ewing's sarcoma family. The prognosis in \ngeneral is poor because of overt metastasis at the time of diagnosis. Of 27 \nreported patients with primitive neuroectodermal tumors of the head and neck, 23 \nwere less than 20 years of age. Most patients presented with a tumor in the \nnasal cavity, paranasal sinuses, or neck. Symptoms developed rapidly (3.6 \nmonths, on average), and a lethal outcome occurred in 9 patients. This highly \nmalignant tumor requires an aggressive combination of radical resection, \nchemotherapy, and radiotherapy. A close follow-up with regular radiographic \nexamination for at least 5 years is mandatory.",
"Chromosome studies were performed on 5 Ewing sarcoma cell lines. An identical \nreciprocal translocation t(11; 22) (q24; q12) was found in 4 cell lines \nestablished from 3 different tumors. These results, associated with those \nobtained at the same time and independently from fresh tumor cells, suggest that \nthe translocation t(11; 22)(q24; q12) may be a chromosomal marker characteristic \nof Ewing sarcoma cells. This translocation involves the chromosome 22 on which \nthe H-c-sis oncogene has been located; it could be used as a new tool for \nexploring the role of genetic transposition in the malignant cell \ntransformation.",
"PURPOSE: To describe a patient with metastasis of Ewing sarcoma to the choroid \nand the molecular genetics of the tumor.\nMETHODS: A 26-year-old woman with metastatic Ewing sarcoma developed large \nchoroidal masses in the left eye and died 2 months later. Autopsy of the eyes \nwas performed. Dual-color fluorescent in situ hybridization was used to detect \ngenetic alteration in the ocular tumor with EWS and FLI-1 probes.\nRESULTS: Histopathology confirmed choroidal metastatic Ewing sarcoma. Molecular \nanalysis showed chromosomal translocation t(11;22)(q24;q12) or EWS/FLI-1 \nrearrangement in the malignant cells of the eye.\nCONCLUSIONS: Ewing sarcoma can rarely metastasize to the uvea. Molecular \ndetection of the t(11;22)(q24;q12) translocation in Ewing sarcoma is valuable in \nthe differential diagnosis of small round cell tumors.",
"The genetic hallmark of the Ewing sarcoma family of tumours (ESFT) is the \npresence of the t(11;22)(q24;q12) translocation, present in up to 85% of cases \nof ESFT, which creates the EWS/FLI1 fusion gene and results in the expression of \na chimeric protein regulating many other genes. The inhibition of this protein \nby antisense strategies has shown its predominant role in the transformed \nphenotype of Ewing cells. In addition, the junction point at the mRNA level \noffers a target for short therapeutic nucleic acids that is present only in the \ncancer cells and not in the normal tissues of a patient. Several teams have, \ntherefore, investigated the activity of antisense oligonucleotides and siRNAs \ntargeted against the junction point in mRNA; thus, inhibiting EWS/FLI1 \nsynthesis. Generally speaking, the molecules induce a cell growth inhibition in \nculture. Apoptosis has also been reported. One laboratory has reported the in \nvivo tumour inhibitory effect of phosphorothioate antisense oligonucleotide \ndirected against the EWS part of EWS/FlI1 when injected intratumourally. \nIndependently, a tumour inhibitory effect of oligonucleotides targeting the \njunction point has been demonstrated provided they are delivered by polymeric \nnanoparticles through the intratumoural route. Alongside this target, other \ngenes participating to the maintenance of the transformed phenotype of Ewing \ncells have been downregulated by antisense strategies.",
"BACKGROUND: Ewing sarcoma is extremely rare in people from East and Southeast \nAsia.\nMETHODS: The records of 12 patients diagnosed with primary Ewing sarcoma and \ntreated at our institution from 1997 to 2009 were retrospectively reviewed.\nRESULTS: There were seven male and five female patients and their mean age at \ndiagnosis was 22 years (range, 12-48 years). Two patients (16.7%) had distant \nmetastasis at diagnosis. The primary tumor sites were the trunk in seven \npatients (58.3%) and the extremities in five patients (41.7%). Eleven patients \nreceived neoadjuvant chemotherapy followed by wide excision surgery, and then \nadjuvant chemotherapy. One patient received only chemotherapy without surgical \nintervention due to poor cardiac and pulmonary function. At a mean follow-up of \n33 months, the 2-year overall survival rate (OS) was 45.5%. Distant metastasis \nwas the only statistically significant prognostic factor of OS in our study. The \n2-year OS rates of patients with lung metastasis and without lung metastasis \nwere 0% and 42.9%, respectively (p = 0.021). The t(11;22)(q24:q12) translocation \nwas present in all patients in our series.\nCONCLUSION: We confirmed that distant metastases is highly predictive of a poor \noutcome, and that the t(11;22)(q24:q12) translocation was present in all \npatients in our series.",
"EWS-Fli1, a fusion gene resulting from a chromosomal translocation t(11;22, \nq24;q12) and found in Ewing sarcoma and primitive neuroectodermal tumors, \nencodes a transcriptional activator and promotes cellular transformation. \nHowever, the precise biological functions of its products remain unknown. To \ninvestigate the role of EWS-Fli1 in cell growth signaling, we transfected Ewing \nsarcoma TC-135 cells with short interfering RNAs for EWS-Fli1. EWS-Fli1 \nknockdown reduced cell growth and platelet-derived growth factor \n(PDGF)-BB-induced activation of the growth signaling enzymes. Interestingly, \nphospholipase D2 (but not the PDGF-BB receptor) showed marked down-regulation in \nthe EWS-Fli1-knocked down TC-135 cells compared with the control cells. In Ewing \nsarcoma TC-135 cells, the PDGF-BB-induced phosphorylation of growth signaling \ninvolving extracellular signal-regulated kinase, Akt, p70S6K, and the expression \nof cyclin D3 were markedly inhibited by transfection with short interfering RNA \nphospholipase (PL)-D2. The PDGF-BB-induced activation of growth signaling was \nalso suppressed by 1-butanol, which prevents the production of phosphatidic acid \nby phospholipase D (but not by t-butyl alcohol), thereby implicating PLD2 in \nPDGF-BB-mediated signaling in TC-135 cells. These results suggest that EWS-Fli1 \nmay play a role in the regulation of tumor proliferation-signaling enzymes via \nPLD2 expression in Ewing sarcoma cells.",
"The hallmark of Ewing's sarcoma (EWS) is a \ntranslocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 \naberrant chimeric gene. Because EWS afflicts young patients, it stands out among \nthe diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic \nchemotherapy regimens produce minimal benefit in patients with metastases at \npresentation or those with relapsed disease. While the outcomes of \nchemorefractory EWS patients are generally poor, recent developments have led to \nthe promising use of targeted therapy. Specifically, inhibition of insulin-like \ngrowth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin \n(mTOR) pathways has emerged as a targeted therapy in EWS, with select patients \nexperiencing dramatic therapeutic responses. However, targeted therapies in \ngeneral, and these responders in particular, are faced with the ultimate \nconundrum of eventual resistance. To optimize response, combining IGF1R and mTOR \ninhibitor-based regimens with chemotherapy in the upfront setting in newly \ndiagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in \nthese patients. Another option is to explore novel targeted multikinase \ninhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have \nexperienced a surge in supporting preclinical data. Drugs inhibiting the \ndownstream targets of EWS/FLI1 are also in preclinical development. However, \nultimately, the underlying biomarker correlates of resistance and response must \nbe delineated along with ways to overcome them. Novel agents, together with \nintegration of advances in multimodal approaches (including surgery and \nradiation), as well as offering targeted therapies early in the disease course \nrepresent new strategies for confronting the challenges of EWS.",
"The presence of t(11;22)(q24;q12) is often considered diagnostic of Ewing \nsarcoma and peripheral primitive neuroectodermal tumor. We report four cases, \nall of which possessed this translocation as detected by reverse transcriptase \npolymerase chain reaction and confirmed by sequencing with or without \nfluorescent in situ hybridization, but none of which were Ewing sarcoma or \nperipheral primitive neuroectodermal tumor by histological criteria. Two were \npolyphenotypic tumors and two were mixed embryonal and alveolar \nrhabdomyosarcomas. Only one case was positive for MIC2 by immunohistochemistry \nand only in a rare cell. Two cases (one polyphenotypic tumor and one \nrhabdomyosarcoma) had double minute chromosomes with > 100 copies of the MDM2 \ngene. The presence of the t(11;22)(q24;ql2) translocation should probably not be \nconsidered diagnostic of Ewing sarcoma and peripheral primitive neuroectodermal \ntumor in the absence of supporting histological evidence. The presence of this \ntranslocation in Ewing sarcoma and peripheral primitive neuroectodermal tumor \nhas been taken as evidence that these two tumors are related. Extending this \nrelationship to include some polyphenotypic tumors and some rhabdomyosarcomas \nmay not be justified unless additional evidence is gathered. Pathologists and \noncologists will need to decide whether treatment regimens for tumors are better \nbased on phenotype rather than genotype when these two profiles are seemingly in \nconflict.",
"The Ewing sarcoma family of tumors (ESFT) includes classic Ewing sarcoma of the \nbone, extraosseous or soft tissue Ewing sarcoma, Askin tumors of the chest wall, \nand peripheral primitive neuroectodermal tumors of the bone and soft tissues. \nThey share a common neural histogenesis, tumor genetics and biology. The genetic \nhallmark of the ESFT is the presence of t(11;22)(q24;q12), which creates the \nEWS/FLI1 fusion gene and results in the expression of a chimeric protein. \nAlthough Ewing tumors can occur at any age, the great majority are found in \nindividuals less than 20 years of age. We herein report a case of gastric Ewing \nsarcoma in a 68-year-old male. This patient illustrates the second reported \noccurrence of primary Ewing sarcoma in the stomach and the first reported with \nthe t(11;22)(q24;q12) gene translocation.",
"Approximately one-third of sarcomas contain specific translocations. Ewing \nsarcoma is the prototypical member of this group of sarcomas; it was the first \nto be recognized pathologically as a singular entity and to have its signature \ntranslocation defined cytogenetically, which led to the identification of its \nkey driver alteration, the EWS-FLI1 gene fusion that encodes this aberrant, \nchimeric transcription factor. We review recent progress in selected areas of \nEwing sarcoma research, including the application of genome-wide chromatin \nimmunoprecipitation analyses, to provide a comprehensive view of the EWS-FLI1 \ntarget gene repertoire, the identification of EWS-FLI1 target genes that may \nalso point to therapeutically targetable pathways, and data from model systems \nas they relate to the elusive cell of origin of Ewing sarcoma and its possible \nsimilarities to mesenchymal stem cells."
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] | train | Which transporter is inhibited by Sotagliflozin? | list | Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2. | ['sodium-glucose co-transporter 1', 'sodium-glucose co-transporter 2'] | [
"Sotagliflozin is a dual sodium-glucose co-transporter-2 and 1 (SGLT2/1) \ninhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). \nSotagliflozin inhibits renal sodium-glucose co-transporter 2 (determining \nsignificant excretion of glucose in the urine, in the same way as other, already \navailable SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose \nabsorption and therefore reducing post prandial glucose. Well-designed clinical \ntrials, have shown that sotagliflozin (as monotherapy or add-on therapy to other \nanti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with \nbeneficial effects on bodyweight and blood pressure. Similar results have been \nobtained in adults with T1D treated with either continuous subcutaneous insulin \ninfusion or multiple daily insulin injections, even after insulin optimization. \nA still ongoing phase 3 study is currently evaluating the effect of \nsotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In \nthis review we illustrate the advantages and disadvantages of dual SGLT 2/1 \ninhibition, in order to better characterize and investigate its mechanisms of \naction and potentialities.",
"Dapagliflozin (SGLT-2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two \nof the drugs of SGLT inhibitor class which have been recommended by the National \nInstitute for Health and Care Excellence (NICE) in people with type 1 diabetes \nwith BMI ≥27 kg/m2 . Dapagliflozin is licensed in the UK for use in the NHS \nwhile sotagliflozin may be available in future. These and possibly other SGLT \ninhibitors may be increasingly used in people with type 1 diabetes as new \nlicences are obtained. These drugs have the potential to improve glycaemic \ncontrol in people with type 1 diabetes with the added benefit of weight loss, \nbetter control of blood pressure and more time in optimal glucose range. \nHowever, SGLT inhibitors are associated with a higher incidence of diabetic \nketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK \njoint updated position statement is to guide people with type 1 diabetes and \nclinicians using these drugs help mitigate this risk and other potential \ncomplications. Particularly, caution needs to be exercised in people who are at \nrisk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, \nstarvation, excessive exercise, excessive alcohol consumption and reduced \ninsulin administration among other precipitating factors for diabetic \nketoacidosis.",
"OBJECTIVE: To assess the safety and efficacy of dual sodium-glucose \ncotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct \ntherapy to insulin in type 1 diabetes.\nRESEARCH DESIGN AND METHODS: We treated 33 patients with sotagliflozin, an oral \ndual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial \nassessing safety, insulin dose, glycemic control, and other metabolic parameters \nover 29 days of treatment.\nRESULTS: In the sotagliflozin-treated group, the percent reduction from baseline \nin the primary end point of bolus insulin dose was 32.1% (P = 0.007), \naccompanied by lower mean daily glucose measured by continuous glucose \nmonitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of \n0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that \nshowed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL \n(9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage \nof time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from \nbaseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = \n0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 \nmmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for \nsotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with \nsotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group.\nCONCLUSIONS: As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with \nsotagliflozin improved glycemic control and the CGM profile with bolus insulin \ndose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.",
"INTRODUCTION: The majority of patients with type 1 diabetes mellitus (T1DM) do \nnot achieve glycemic targets. In addition, treatment with insulin is associated \nwith increased risk for hypoglycemia and weight gain. Accordingly, there is an \nunmet need for new safe and effective glucose-lowering agents in this \npopulation. Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 \nand 2, has been recently approved for use in patients with T1DM.\nAREAS COVERED: The authors review the major trials that have evaluated the \nsafety and efficacy of sotagliflozin and provide their expert opinion.\nEXPERT OPINION: Even though sotagliflozin reduces HbA1 c levels and does not \nappear to increase the risk for hypoglycemia in most patients, the substantially \nincreased risk for diabetic ketoacidosis limits the use of this agent to a \ncarefully selected subgroup of patients with T1DM. Based on the existing \nevidence, sotagliflozin should be considered only in patients who have failed to \nachieve adequate glycemic control despite optimal insulin therapy, are at low \nrisk for diabetic ketoacidosis, have been adequately trained to recognize this \ncomplication and are able to be in close contact with their physician.",
"Cardiovascular diseases are the leading cause of morbidity and mortality in the \nworld. Diabetes increase heart disease related to death by two- to four-fold. \nSGLT2 inhibitors are new antidiabetic agents. The growing evidence of \ncardiovascular benefit of SGLT2 inhibitors independent of their effects on \nglycemic control is especially intriguing. Several clinical trials have shown \nthat sotagliflozin (SGLT1-1/2 inhibitor) decreases body weight and reduces blood \npressure in adults with T2D. A phase 3 study designed to evaluate cardiovascular \noutcomes of sotagliflozin is currently ongoing. Many pre-clinical studies were \nconducted to investigate the potential mechanisms involved in cardiovascular \nbenefits of SGLT1 or SGLT2 inhibition with or without diabetes. Although \nmultiple mechanisms have been proposed, there are still not enough data to fully \nsupport the mechanisms of actions. This review aims to discuss the potential \nmechanisms involved in cardiovascular benefits of SGLT1 and SGLT2 inhibition in \nboth diabetic and non-diabetic states.",
"OBJECTIVE: Evaluate the efficacy and safety of the dual sodium-glucose \ncotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with \noptimized insulin in type 1 diabetes (T1D).\nRESEARCH DESIGN AND METHODS: The inTandem1 trial, a double-blind, 52-week phase \n3 trial, randomized North American adults with T1D to placebo (n = 268), \nsotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) after 6 weeks \nof insulin optimization. The primary end point was HbA1c change from baseline at \n24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks.\nRESULTS: From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were \n0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and \n0.25% and 0.31% at 52 weeks (all P < 0.001). Among patients with a baseline \nHbA1c ≥7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients \nreceiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively \n(P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences \nbetween sotagliflozin 400 mg and placebo were -1.08 mmol/L for fasting plasma \nglucose, -4.32 kg for weight, and -15.63% for bolus insulin dose and -11.87% for \nbasal insulin dose (all P < 0.001). Diabetes Treatment Satisfaction \nQuestionnaire scores increased significantly by 2.5 points with sotagliflozin \nversus placebo (P < 0.001) at 24 weeks. Genital mycotic infections and diarrhea \noccurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis \n(DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 \nand 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia \noccurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) \npatients receiving placebo.\nCONCLUSIONS: In a 1-year T1D study, sotagliflozin combined with optimized \ninsulin therapy was associated with sustained HbA1c reduction, weight loss, \nlower insulin dose, fewer episodes of severe hypoglycemia, improved \npatient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, \nNCT02384941).",
"The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important \nemerging class for the treatment of diabetes. Development of SGLT2 inhibitors \nhas been oriented around a desire for high selectivity for the SGLT2 protein \nrelative to the SGLT1 protein. More recently, genetic and pharmacology research \nin mice has indicated that gastrointestinal SGLT1 inhibition may also be an \nappropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 \ninhibition in a single molecule would provide complementary insulin-independent \nmechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been \ndeveloped as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical \nfeatures of dual inhibitor of SGLT1 and SGLT2 include a large postprandial \nglucose reduction, elevation of glucagon-like peptide 1 and modest urinary \nglucose excretion. These features may have clinical implications for the use of \nsotagliflozin in the treatment of both type 1 and type 2 diabetes.",
"BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is \nnot achieved with insulin therapy alone. We evaluated the safety and efficacy of \nsotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in \ncombination with insulin treatment in patients with type 1 diabetes.\nMETHODS: In this phase 3, double-blind trial, which was conducted at 133 centers \nworldwide, we randomly assigned 1402 patients with type 1 diabetes who were \nreceiving treatment with any insulin therapy (pump or injections) to receive \nsotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point \nwas a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of \nsevere hypoglycemia or diabetic ketoacidosis after randomization. Secondary end \npoints included the change from baseline in glycated hemoglobin level, weight, \nsystolic blood pressure, and mean daily bolus dose of insulin.\nRESULTS: A significantly larger proportion of patients in the sotagliflozin \ngroup than in the placebo group achieved the primary end point (200 of 699 \npatients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change \nfrom baseline was significantly greater in the sotagliflozin group than in the \nplacebo group for glycated hemoglobin (difference, -0.46 percentage points), \nweight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus \ndose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of \nsevere hypoglycemia was similar in the sotagliflozin group and the placebo group \n(3.0% [21 patients] and 2.4% [17], respectively). The rate of documented \nhypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per \nliter) or below was significantly lower in the sotagliflozin group than in the \nplacebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin \ngroup than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively).\nCONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the \nproportion of patients who achieved a glycated hemoglobin level lower than 7.0% \nwith no severe hypoglycemia or diabetic ketoacidosis was larger in the group \nthat received sotagliflozin than in the placebo group. However, the rate of \ndiabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon \nPharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).",
"BACKGROUND: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has \nbeen shown to reduce cardiovascular mortality in heart failure independently of \nglycemic control and prevents the onset of atrial arrhythmias, a common \nco-morbidity in heart failure with preserved ejection fraction (HFpEF). The \nmechanism behind these effects is not fully understood, and it remains unclear \nif they could be further enhanced by additional SGLT-1 inhibition. We \ninvestigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor \nsotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. \natrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.\nMETHODS: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of \nHFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for \n6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ \ntransients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ \nrelease were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent \ndyes (Fura-2) during various experimental protocols. Mitochondrial structure \n(dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial \ndepolarization (dye: TMRE) and production of reactive oxygen species (dye: \nH2DCF) were visualized by confocal microscopy. Statistical analysis was \nperformed with 2-way analysis of variance followed by post-hoc Bonferroni and \nstudent's t-test, as applicable.\nRESULTS: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA \ncardiomyocytes in HFpEF showed an increased incidence and amplitude of \narrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly \nreduced the magnitude of SCaEs, while their frequency was unaffected. \nSotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to \nglucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium \nexchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial \nswelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin \nimproved mitochondrial fission and reactive oxygen species (ROS) production \nduring glucose starvation and averted Ca2+ accumulation upon glycolytic \ninhibition.\nCONCLUSION: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in \nmetabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular \narrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer \ncapacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of \ncombined SGLT-1&2 inhibition for the treatment and/or prevention of atrial \ncardiomyopathy associated arrhythmias should be further evaluated in clinical \ntrials.",
"Diabetes mellitus is the global health issue and become an alarming threat in \nthe modern era where human lifestyle gets compromised with modernization. \nAccording to the latest statistical report 2020, USA has 9.47% (31 million among \n32.72 cr), China has 8.3% (116.4 million among 139.27 cr) and India has 5.6% (77 \nmillion among 135.26 cr) of the diabetic people, indicating that diabetes is \nmore prevailing in developed countries as compared to the developing countries. \nThe number of diabetic patients is rising day by day at a tremendous rate and \nsoon it may affect each and every person in a family. So, there is an urgent \nneed to develop novel entities that can meet the scarcity of present \nantidiabetic agents. In the last few decades, the sodium-glucose co-transporter \n2 (SGLT2) has emerged as a prominent target for the treatment of Type 2 diabetes \nmellitus due to its novel mechanism of action & no involvement in insulin \nsignaling pathway. Most of the inhibitors that target SGLT2 contain three basic \nmoieties: glucose, two benzene rings (one is connected with glucose and the \nother with methylene), and the methylene bridge which are similar to \ndapagliflozin. Several SGLT2 inhibitors and their derivatives such as \nremogliflozin etabonate (phase-II), sotagliflozin (phase-III) and bexagliflozin \n(phase-III) are under different phases of clinical trial studies and some have \nbeen patented. The present review is focused on SGLT2 inhibitors, structure \nactivity relationships (SARs) of dapagliflozin and its several analogues for \ntheir binding affinity with SGLT2. We have also presented and summarized the \nefforts made by various researchers in terms of the synthesis of various \ndapagliflozin derivatives till date.",
"Sotagliflozin is a dual sodium-glucose co-transporter (SGLT) 2 inhibitor, \nmanifesting a 20-fold higher inhibitory activity for SGLT2 than for SGLT1. \nDifferences in SGLT2 over SGLT1 selectivity of the available agents have been \nproposed to relate to variability in efficacy and safety characteristics. In \ncontrast to other SGLT2 inhibitors, the cardiorenal effects of sotagliflozin in \ntype 2 diabetes had not been explored until recently, when the results of \nSOLOIST-WHF (focusing on heart failure [HF] outcomes) and SCORED (focusing on \nrenal outcomes) were published. In SOLOIST-WHF, sotagliflozin reduced the risk \nof the primary composite outcome of cardiovascular (CV) death and \nhospitalizations and urgent visits for HF. The findings showed that the risk \nreduction was consistent in people with reduced but also in those with preserved \nejection fraction (EF). In SCORED, sotagliflozin significantly reduced the \nprimary end point of CV deaths, hospitalizations for HF, and urgent visits for \nHF. A reduction in glycated hemoglobin was evident even in participants with \nestimated glomerular filtration rate values below 30 mL/min/1.73 m2. SCORED is \nalso the first trial to illustrate the benefits of the class across the full \nrange of albuminuria. Moreover, the endpoint of stroke was significantly reduced \nby 34% in the sotagliflozin compared with the placebo group. The findings of the \ntwo studies provide novel insights into the clinical utility of SGLT2 \ninhibitors, particularly with respect to the early initiation in stable HF, the \nbenefits in HF with preserved EF, the glucose-lowering efficacy in people with \nsevere renal impairment and their potential to improve atherosclerotic vascular \ndisease, including stroke, outcomes.",
"Sotagliflozin (Zynquista™) is a dual inhibitor of sodium-glucose co-transporters \n(SGLT) 1 and 2 being developed by Lexicon Pharmaceuticals and Sanofi as a \ntreatment for type 1 (T1DM) and type 2 diabetes mellitus (T2DM). The drug has a \ndual action, blunting and delaying absorption of glucose from the \ngastrointestinal tract and the reabsorption of glucose in the proximal tubule of \nthe kidney, respectively. In the phase III inTandem clinical trial program in \npatients with T1DM, sotagliflozin as an adjunct to optimised insulin therapy \nproduced a clinically meaningful reduction in HbA1c levels, but was associated \nwith a higher incidence of diabetic ketoacidosis than placebo. Sotagliflozin was \nrecently approved for use as an adjunct to insulin in T1DM in the EU. However, \nthe FDA Endocrinologic and Metabolic Drugs Advisory Committee was divided, \nciting concerns regarding diabetic ketoacidosis, leading the FDA to issue an \nComplete Response Letter for this indication in the USA. This article summarizes \nthe milestones in the development of sotagliflozin leading to this first \napproval in the EU as an adjunct to insulin in patients with T1DM with a body \nmass index ≥ 27 kg/m2 who have failed to achieve adequate glycaemic control \ndespite optimal insulin therapy.",
"Publisher: Chronisch nierenkranke Patienten weisen eine erhöhte kardiovaskuläre \nMorbidität und Sterblichkeit auf. Im letzten Jahr sind einige wichtige Studien \nzur Herz-Nieren-Interaktion veröffentlicht worden, die im Folgenden \nzusammengefasst und diskutiert werden. In der DAPA-CKD-Studie sowie in der \nSCORED-Studie konnten 2 unterschiedliche SGLT2(„sodium-glucose linked \ntransporter 2“)-Inhibitoren (Dapagliflozin und Sotagliflozin) die Prognose von \nchronisch nierenkranken Patienten mit und ohne Diabetes nachweislich verbessern. \nAuch die Ergebnisse der randomisierten Studie zum neuen \nMineralokortikoidrezeptorantagonisten Finerenon – FIDELIO-DKD – liefern einen \nvielversprechenden neuen Therapieansatz für Patienten mit diabetischer \nNephropathie. Die veröffentlichten Daten der ISCHEMIA-CKD-Studie bei Patienten \nmit koronarer Herzkrankheit und Untersuchungen zum Einfluss einer TAVI \n(„transcatheter aortic valve implantation“) auf die Nierenfunktion sowie eine \nweitere Studie zum akuten Nierenversagen nach MitraClip®-Implantation (Abbott, \nChicago, IL, USA) geben wichtige Hinweise zu zukünftigen Handlungsempfehlungen. \nDer optimale Zeitpunkt der Einleitung einer Nierenersatztherapie bei Patienten \nmit akuter Nierenschädigung in der Intensivmedizin wurde in 2 randomisierten \nStudien untersucht, die entsprechend diskutiert werden.",
"Two large-scale mouse gene knockout phenotyping campaigns have provided \nextensive data on the functions of thousands of mammalian genes. The ongoing \nInternational Mouse Phenotyping Consortium (IMPC), with the goal of examining \nall ∼20,000 mouse genes, has examined 5115 genes since 2011, and phenotypic data \nfrom several analyses are available on the IMPC website \n(www.mousephenotype.org). Mutant mice having at least one human genetic \ndisease-associated phenotype are available for 185 IMPC genes. Lexicon \nPharmaceuticals' Genome5000™ campaign performed similar analyses between 2000 \nand the end of 2008 focusing on the druggable genome, including enzymes, \nreceptors, transporters, channels and secreted proteins. Mutants (4654 genes, \nwith 3762 viable adult homozygous lines) with therapeutically interesting \nphenotypes were studied extensively. Importantly, phenotypes for 29 Lexicon \nmouse gene knockouts were published prior to observations of similar phenotypes \nresulting from homologous mutations in human genetic disorders. Knockout mouse \nphenotypes for an additional 30 genes mimicked previously published human \ngenetic disorders. Several of these models have helped develop effective \ntreatments for human diseases. For example, studying Tph1 knockout mice (lacking \nperipheral serotonin) aided the development of telotristat ethyl, an approved \ntreatment for carcinoid syndrome. Sglt1 (also known as Slc5a1) and Sglt2 (also \nknown as Slc5a2) knockout mice were employed to develop sotagliflozin, a dual \nSGLT1/SGLT2 inhibitor having success in clinical trials for diabetes. Clinical \ntrials evaluating inhibitors of AAK1 (neuropathic pain) and SGLT1 (diabetes) are \nunderway. The research community can take advantage of these unbiased analyses \nof gene function in mice, including the minimally studied 'ignorome' genes.",
"The sodium-glucose cotransporter type 1 (SGLT1) is the primary transporter for \nabsorption of glucose and galactose in the gastrointestinal tract. Inhibition \nblunts and delays postprandial glucose (PPG) excursion. Sodium-glucose \ncotransporter type 2 (SGLT2) is expressed in the kidney, where it reabsorbs 90% \nof filtered glucose. Thus, a dual SGLT1 and SGLT2 inhibition (compared with \nselective SGLT2 inhibition) could result in lower PPG and robust A1c reduction \neven in patients with reduced kidney function. Sotagliflozin is an oral potent \ndual inhibitor of the insulin-independent SGLT1 and SGLT2. Preliminary data \nreleased from phase 2 and 3 clinical studies in adults with type 1 diabetes \nmellitus (T1DM) and type 2 diabetes mellitus (T2DM) showed improved glycemic \ncontrol, and met efficacy endpoints beyond A1c with a safety profile consistent \nwith the SGLT class: significant reduction in body weight, systolic blood \npressure, and efficacy maintained in lower estimated glomerular filtration rate \nlevels with no increased hypoglycemia. Increased risk of diabetic ketoacidosis \n(DKA) with uncharacteristically mild-to-moderate glucose elevations (euglycemic \nDKA) is associated with the use of all the approved SGLT2 inhibitors. Factors \nthat trigger DKA include insulin reductions, low caloric and fluid intake, \nintercurrent illness, and alcohol use. However, DKA is detectable and manageable \nwith proper patient education. With sotagliflozin, DKA rates were not higher \nthan the expected background rate in T1DM, but numerically higher than placebo. \nSotagliflozin is the first oral SGLT1 and SGLT2 inhibitor developed for the \ntreatment of adult patients with T1DM, in adjunct with insulin, and has the \npotential to address unmet needs for patients with T1DM and possibly T2DM, with \na favorable benefit/risk profile.",
"Sotagliflozin (Zynquista™) is the first dual inhibitor of sodium-glucose \nco-transporter-1 and -2 (SGLT1 and 2). In the phase 3, inTANDEM 1-3 trials, \nadjunctive use of oral sotagliflozin (200 mg or 400 mg once daily) improved \nglycaemic control and reduced bodyweight and insulin requirements relative to \nplacebo over 24 weeks of treatment in adults whose type 1 diabetes (T1D) was \ninadequately controlled by insulin therapy. Similar benefits were seen with the \ndrug in patients who were overweight/obese [i.e. body mass index (BMI) \n≥ 27 kg/m2] in inTANDEM 1 and 2 (pooled). The benefits of sotagliflozin were \nlargely maintained over 52 weeks of treatment. Overall, use of sotagliflozin in \nthis setting is generally well tolerated and reduces, or at least does not \nincrease, the likelihood of hypoglycaemia; however, as with other SGLT \ninhibitors, sotagliflozin carries a risk of diabetic ketoacidosis (DKA). On the \nbasis of its risk/benefit profile, sotagliflozin is indicated in the EU as an \nadjunct to insulin in adults with T1D with a BMI ≥ 27 kg/m2 who have failed to \nachieve adequate glycaemic control despite optimal insulin therapy, thus \nexpanding the currently limited adjunctive oral treatment options available for \nuse in this population.",
"INTRODUCTION: SGLT1 is the primary transporter responsible for the absorption of \nglucose and galactose in the intestine, while SGLT2 and SGLT1 are both involved \nin the renal reabsorption of glucose. SGLT2 inhibitors are a new class of oral \nantidiabetic drugs, acting by increasing urinary glucose excretion (UGE). They \noffer the advantages of a reduced risk of hypoglycaemia, a decrease in body \nweight and blood pressure and an efficacy at all stages of type 2 diabetes \n(T2DM).\nAREAS COVERED: Herein, the authors focus specifically on sotagliflozin (LX4211), \nthe first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English \nwere selected as the basis of this review. Clinical trials were identified using \nthe Clinicaltrial.gov database.\nEXPERT OPINION: By a potential additional mechanism of action on intestinal \nglucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from \nSGLT2 inhibitors by reducing postprandial glucose excursion and insulin \nsecretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on \nUGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 \ninhibitors on HbA1C reduction, with a similar safety profile in short-term \nstudies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 \ndevelopment as an adjuvant treatment in patients with T1DM after positive \nresults from a pilot study.",
"CONTEXT: The effect of sotagliflozin (a dual sodium-glucose cotransporter [SGLT] \n2 and SGLT1 inhibitor) on intestinal glucose absorption has not been \ninvestigated in humans.\nOBJECTIVE: To measure rate of appearance of oral glucose (RaO) using a dual \nglucose tracer method following standardized mixed meals taken after single \nsotagliflozin or canagliflozin doses.\nSETTING: Clinical research organization.\nDESIGN AND PARTICIPANTS: In a double-blind, 3-period crossover study \n(NCT01916863), 24 healthy participants were randomized to 2 cohorts of 12 \nparticipants. Within each cohort, participants were randomly assigned single \noral doses of either sotagliflozin 400 mg, canagliflozin 300 mg, or placebo on \neach of test days 1, 8, and 15. On test days, Cohort 1 had breakfast containing \n[6,6-2H2] glucose 0.25 hours postdose and lunch containing [1-2H1] glucose 5.25 \nhours postdose; Cohort 2 had breakfast containing no labeled glucose 0.25 hours \npostdose and lunch containing [6,6-2H2] glucose 4.25 hours postdose. All \nparticipants received a 10- to 15-hour continuous [U-13C6] glucose infusion \nstarting 5 hours before their first [6,6-2H2] glucose-containing meal.\nMAIN OUTCOME: RaO, postprandial glucose (PPG), and postprandial insulin.\nRESULTS: Sotagliflozin and canagliflozin decreased area under the curve (AUC)0-1 \nhour and/or AUC0-2 hours for RaO, PPG, and insulin after breakfast and/or the \n4.25-hour postdose lunch (P < .05 versus placebo). After the 5.25-hour postdose \nlunch, sotagliflozin lowered RaO AUC0-1 hour and PPG AUC0-5 hours versus both \nplacebo and canagliflozin (P < .05).\nCONCLUSIONS: Sotagliflozin delayed and blunted intestinal glucose absorption \nafter meals, resulting in lower PPG and insulin levels, likely due to prolonged \nlocal inhibition of intestinal SGLT1 that persisted for ≥5 hours after dosing.",
"Sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1/SGLT2 inhibitor, is \ncurrently approved in Europe as an adjunct to optimal insulin therapy in adults \nwith type 1 diabetes (T1D) and a body mass index (BMI) ≥ 27 kg/m2 . In this post \nhoc analysis, efficacy at 24 weeks and safety at 52 weeks from pooled phase 3 \nclinical trials were evaluated in patients with baseline BMI ≥ 27 kg/m2 . \nSotagliflozin 200 mg and 400 mg added to insulin reduced glycated haemoglobin \nlevel and increased time in range assessed by continuous glucose monitoring \nversus placebo and also reduced body weight and systolic blood pressure. \nDifferences in efficacy endpoints between sotagliflozin and placebo tended to be \ngreater among patients with BMI ≥ 27 kg/m2 compared to those with baseline BMI \n< 27 kg/m2 . Consistent with published results for the entire population, fewer \nsevere hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a \nhigher incidence of diabetic ketoacidosis occurred with sotagliflozin versus \nplacebo in patients with BMI ≥ 27 kg/m2 . Sotagliflozin as an adjunct to \noptimized insulin therapy in overweight/obese patients with T1D addressed some \nunmet needs and may help achieve optimal glycaemic control, mitigating weight \ngain without increasing hypoglycaemia risk in this high-risk population.",
"In spite of developments with novel insulin preparations, novel modes of insulin \ndelivery with insulin infusion pumps, and the facility of continuous glucose \nmonitoring, only 20% of patients with type 1 diabetes are under adequate \ncontrol. The need for innovation is clear, and, therefore, the use of adjunct \ntherapies with other pharmacological agents currently in use for type 2 \ndiabetes, has been tried. Currently, pramlintide is the only agent licensed for \nuse in this condition in addition to insulin. Global trials have been conducted \nwith liraglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), \ndapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and \nsotagliflozin, an inhibitor of both SGLT1 and SGLT2 transporters. While \ndapagliflozin and sotagliflozin have now been licensed for clinical use in this \ncondition in Europe and Japan, they have hitherto not been licensed in the \nUnited States due to a small increase in the risk of diabetic ketoacidosis. \nHowever, these agents reduce glycosylated hemoglobin (HbA1c) by 0.4%, reduce \nglycemic oscillations, and do not increase the risk of hypoglycemia. \nLiraglutide, on the other hand, induced a smaller reduction in HbA1c and thus \nwas not considered for a license. However, further trials are currently being \nconducted with a combination of semaglutide, the most potent GLP-1RA, and \ndapagliflozin to determine whether this approach would yield better outcomes.",
"Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in \ndiabetes. Sotagliflozin blocks SGLT2 in the kidneys and SGLT1 in the intestines \nresulting in reduced early phase glucose absorption and increased blood levels \nof GLP-1 and PYY. Urinary glucose excretion is lower than with other agents as a \nresult of decreased glucose absorption. The primary development effort to date \nhas been in Type 1 diabetes. Areas covered: The published information on \nsotagliflozin is reviewed, along with the recent results of several pivotal Type \n1 diabetes trials. Expert opinion: Sotagliflozin treatment lowers HbA1c and \nreduces glucose variability, with a trend to less hypoglycemic events. In the \nType 1 trials, sotagliflozin treated individuals experienced DKA at a higher \nrate than placebo treated patients. An additional safety issue arises from the \nas yet unknown potential risks in women of child bearing potential in whom DKA \nis of utmost concern. The sotagliflozin development program has now been \nextended to trials in Type 2 diabetes, and long term studies will be needed to \nassess the benefits and risks of the agent in comparison to other currently \nmarketed SGLT2 inhibitors.",
"AIMS: To evaluate the evidence for the novel dual sodium-glucose \nco-transporter-1 (SGLT1) and -2 (SGLT2) inhibitor, sotagliflozin, which may \nenhance the efficacy of SGLT2 inhibitors by additionally reducing intestinal \nglucose absorption.\nMETHODS: The search terms 'sotagliflozin', 'LX4211', 'SGLT' and 'diabetes' were \nentered into PubMed. Evidence for the pharmacokinetics, pharmacodynamics, safety \nand efficacy of sotagliflozin in Type 1 and 2 diabetes was extracted from the \nretrieved literature, critically evaluated, and contextualized in relation to \ndata on existing SGLT2 inhibitors.\nRESULTS: There is convincing evidence from a range of phase II and III clinical \ntrials that sotagliflozin significantly improves glycaemic control in both Type \n1 and Type 2 diabetes. Additional benefits, such as smaller postprandial plasma \nglucose excursions, lower insulin requirements, appetite suppression and weight \nloss have been documented. While this is encouraging, several safety concerns \nremain; a dose-dependent increase in the rate of diabetic ketoacidosis, \ndiarrhoea and genital mycotic infection is apparent, although statistical \nexploration of the data regarding such events is currently lacking. \nSpeculatively, use of a 200-mg rather than a 400-mg dose may help to limit \nunwanted effects.\nCONCLUSIONS: The current evidence for sotagliflozin in diabetes appears \npromising. Further studies sufficiently powered to assess present and emerging \nsafety concerns, as well as to identify individuals for whom sotagliflozin may \nbe of particular benefit/harm would now be informative for regulatory \ndecision-making. Direct comparisons with existing SGLT2 inhibitors are also \nneeded to determine relative safety/efficacy profiles for the different \nindications.",
"AIMS: To identify and synthesize phase 3 and phase 4 randomized controlled \ntrials (RCTs) of sodium-glucose co-transporter (SGLT) inhibitors and metformin \nas adjuncts to insulin in type 1 diabetes (T1DM) using network meta-analysis \n(NMA).\nMATERIALS AND METHODS: A systematic literature review (SLR) identified relevant \nRCTs of ≥12 Weeks duration. MEDLINE, Embase, the Cochrane Library and grey \nliterature were searched through October 2018. NMAs indirectly compared SGLT \ninhibitors and metformin for change from baseline in HbA1c, weight, total daily \ninsulin dose and systolic blood pressure at Week 24 to 26 and Week 52. Safety \noutcomes were also explored.\nRESULTS: Nine trials (N = 6780) were included in the SLR. NMAs indicated that \nall therapies performed better than placebo for the efficacy outcomes at both \ntime points. Compared with metformin at Week 24 to 26, the SGLT inhibitors \ndapagliflozin (5 mg), sotagliflozin (200 mg) and empagliflozin (10 mg) had \nlarger reductions in HbA1c (mean difference [MD] = -0.24, 95% credible interval \n[CrI], -0.41 to -0.07, MD = -0.23, 95% CrI, -0.39 to -0.08 and MD = -0.35, 95% \nCrI, -0.51 to -0.19, respectively) and in weight, which were sustained in \nsensitivity analyses. There were few differences observed in the results of \nsafety outcomes, such as risk of diabetic ketoacidosis (DKA), which should be \ninterpreted cautiously because of wide CrIs.\nCONCLUSIONS: Adjunctive use of SGLT inhibitors in T1DM can improve glycaemic \ncontrol compared with metformin while enabling weight loss, with consistent \nefficacy across the class. However, these results are based on indirect evidence \nso confirmation in a head-to-head study would be valuable.",
"Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) are the two \ndisorders which are known to share pertinent pathological and therapeutic links. \nSodium glucose co-transporter-2 (SGLT2) and Acetylcholinesterase (AChE) are \nestablished inhibition targets for T2DM and AD treatments, respectively. Reports \nsuggest that anti-diabetic drugs could be used for AD treatment also. The \npresent study used molecular docking by Autodock4.2 using our \n\"Click-By-Click\"-protocol, Ligplot1.4.3 and \"change in accessible surface area \n(ΔASA)-calculations\" to investigate the binding of two investigational \nanti-diabetic drugs, Ertugliflozin and Sotagliflozin to an established target \n(SGLT2) and a research target (human brain AChE). Sotagliflozin appeared more \npromising for SGLT2 as well as AChE-inhibition with reference to ΔG and Ki \nvalues in comparison to Ertugliflozin. The ΔG and Ki values for \n\"Sotagliflozin:AChE-binding\" were -7.16 kcal/mol and 5.6 μM, respectively while \nthe same were found to be -8.47 kcal/mol and 0.62 μM, respectively for its \ninteraction with SGLT2. Furthermore, \"Sotagliflozin:SGLT2-interaction\" was \nsubjected to (un)binding simulation analyses by \"Molecular-Motion-Algorithms.\" \nThis information is significant as the exact binding mode, interacting amino \nacid residues and simulation results for the said interaction have not been \ndescribed yet. Also no X-ray crystal is available for the same. Finally, the \nresults described herein indicate that Sotagliflozin could have an edge over \nErtugliflozin for treatment of Type 2 diabetes. Future design of drugs based on \nSotagliflozin scaffolds for treatment of Type 2 and/or Type 3 diabetes are \nhighly recommended. As these drugs are still in late phases of clinical trials, \nthe results described herein appear timely. J. Cell. Biochem. 118: 3855-3865, \n2017. © 2017 Wiley Periodicals, Inc.",
"A mild and convenient method for the synthesis of reverse glycosyl fluorides \n(RGFs) has been developed that is based on the silver-promoted radical \ndehydroxymethylative fluorination of carbohydrates. A salient feature of the \nreaction is that furanoid and pyranoid carbohydrates furnish structurally \ndiverse RGFs bearing a wide variety of functional groups in good to excellent \nyields. Intramolecular hydrogen atom transfer experiments revealed that the \nreaction involves an underexploited radical fluorination that proceeds via \nβ-fragmentation of sugar-derived primary alkoxyl radicals. Structurally \ndivergent RGFs were obtained by catalytic C-F bond activation, and our method \nthus offers a concise and efficient strategy for the synthesis of reverse \nglycosides by late-stage diversification of RGFs. The potential of this method \nis showcased by the preparation and diversification of sotagliflozin, leading to \nthe discovery of a promising SGLT2 inhibitor candidate."
] | nan |
550313aae9bde6963400001f | [
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21052952,
1689595,
16822461
] | train | Which treatment leads to an increase in neutrophil counts in severe congenital neutropenia? | summary | In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections | In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections | [
"Congenital neutropenias include a heterogenous group of diseases characterized \nby a decrease in circulating neutrophils. In phase I/II/III studies in patients \nwith severe congenital and cyclic neutropenia, treatment with recombinant human \ngranulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the \nabsolute neutrophil counts (ANC) and a reduction in infections. We report the \neffects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 \npatients (congenital n = 44. cyclic n = 10) treated for 4-6 years. A sustained \nANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 \ncyclic neutropenia patients. Two patients required an increase of > 25% in dose \nto maintain a clinical response; one patient became refractory to therapy. A \nsignificant decrease in the incidence of severe infections and the need for \nintravenous antibiotics was noted. Significant adverse events noted which may or \nmay not be related to therapy included: osteopenia (n = 15), splenomegaly (n = \n12), hypersplenism (n = 1), vasculitis (n = 2), glomerulonephritis (n = 1), BM \nfibrosis (n = 2), MDS/leukaemia (n = 3), and transient inverted chromosome 5q \nwith excess blasts (n = 1). R-metHuG-CSF has been well tolerated in the majority \nof patients and resulted in a long-term improvement in their clinical status.",
"Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized \nby severe neutropenia or absence of blood neutrophils secondary to a \nmaturational arrest at the level of promyelocytes. We examined peripheral blood \nmononuclear cells (PBMC) of SCN patients who demonstrated normalization of their \nblood neutrophil counts in a phase II clinical study with recombinant human \ngranulocyte colony-stimulating factor (rhG-CSF). When stimulated in vitro with \nbacterial lipopolysaccharides (LPS), PBMC of those SCN patients produced G-CSF \nactivity, as judged by proliferation induction of the murine leukemia cell line, \nNFS-60. Western and Northern blot analysis showed G-CSF protein and G-CSF-mRNA \nindistinguishable in size from those of normal controls. We conclude that PBMC \nof the SCN patients tested are capable of synthesizing and secreting \nbiologically active G-CSF in vitro.",
"STUDY OBJECTIVE: To define the clinical and hematologic effects of recombinant \nhuman granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on patients \nwith chronic severe neutropenia.\nDESIGN: Open-label, phase II study of rhGM-CSF.\nSETTING: Inpatient hematology and surgery clinic at a university medical center.\nPATIENTS: Four consecutive patients with chronic severe neutropenia, which in \ntwo cases was complicated by severe infection, in one case by perianal fistula, \nand in one case by complete rectal prolapse. Two patients had chronic idiopathic \nneutropenia; one patient had congenital neutropenia (myelokathexis); and one \npatient had autoimmune neutropenia.\nINTERVENTIONS: The rhGM-CSF was given intravenously or subcutaneously at \nstarting dosages of 150 to 1000 micrograms/m2 body surface area.d for 12 to 14 \nconsecutive days. Two patients received a second course of daily rhGM-CSF \ntreatment after a nontreatment interval of 14 to 20 days.\nMEASUREMENTS AND MAIN RESULTS: In all four patients, the absolute neutrophil \ncounts increased from less than 0.25 x 10(9)/L to 3.2 to 19.2 x 10(9)/L within 2 \nweeks of beginning rhGM-CSF therapy. Two patients had life-threatening \ninfections that resolved during therapy. The two other patients had major \nano-rectal surgery during rhGM-CSF treatment and had no postoperative \ninfections.\nCONCLUSIONS: In patients with chronic neutropenia, rhGM-CSF may increase \nneutrophil counts. This therapy may be a useful adjunct to antibiotic therapy \nfor patients with infection and perioperatively for patients having anorectal \nsurgery.",
"Severe congenital neutropenia (SCN) or Kostmann syndrome is a disorder of \nmyelopoiesis characterized by a maturation arrest at the stage of promyelocytes \nor myelocytes in bone marrow and absolute neutrophil counts less than 200/microL \nin peripheral blood. Treatment of these patients with granulocyte \ncolony-stimulating factor (G-CSF) leads to a significant increase in circulating \nneutrophils and a reduction in infection-related events in more than 95% of the \npatients. To date, little is known regarding the underlying pathomechanism of \nSCN. G-CSF-induced neutrophils of patients with SCN are functionally defective \n(eg, chemotaxis, superoxide anion generation, Ca(++ )mobilization). Two \nguanosine triphosphatases (GTPases), Rac2 and RhoA, were described to be \ninvolved in many neutrophil functions. The expression of these GTPases and their \nregulation in patients' neutrophils were of interest. This study determined that \nthe guanosine diphosphate (GDP)-dissociation inhibitor RhoGDI is overexpressed \nat the protein level in patients' neutrophils and that overexpression is a \nresult of G-CSF treatment. RhoA and LyGDI are expressed at similar levels, \nwhereas Rac2 shows a decreased expression. In addition, association of Rac2 and \nRhoGDI or LyGDI is abrogated or not detectable based on the low Rac2 expression \nin patients' neutrophils. (Blood. 2000;95:2947-2953)",
"Patients with severe chronic neutropenia have blood neutrophil level <0.5 × \n10(9)/L, predisposing them to increased susceptibility to life-threatening \nbacterial infections. This chapter focuses on cyclic and congenital neutropenia, \ntwo very interesting and rare hematological conditions causing severe chronic \nneutropenia. Both disorders respond well to treatment with the myeloid growth \nfactor, granulocyte colony-stimulating factor (G-CSF). This chapter describes \nthe basic features of these diseases and addresses several current clinical \nissues regarding their diagnosis and management. Cyclic neutropenia is a rare, \ninherited autosomal dominant disorder due to mutations in the gene for \nneutrophil elastase (ELA-2 or ELANE). Usually these patients have regular \noscillation of blood neutrophil counts with periods of severe neutropenia \noccurring every 21 days. During these periods, they have painful mouth ulcers, \nfevers, and bacterial infections. The most severe consequences are gangrene, \nbacteremia, and septic shock. Cyclic neutropenia patients respond well to \ntreatment with granulocyte colony-stimulating factor (G-CSF) given by \nsubcutaneous injections on a daily or alternate-day basis. Severe congenital \nneutropenia is also a rare hematological disease, but it is probably more common \nthan cyclic neutropenia. Blood neutrophils are extremely low on a continuing \nbasis; the levels may be <0.2 × 10(9)/L, and the risk of severe bacterial \ninfections is even greater than in cyclic neutropenia. The majority of cases are \ndue to autosomal dominant inheritance of mutations in the ELA-2 or ELANE gene. \nLess commonly, mutations in HAX-1, G6PC3, and other genes cause this disorder. \nTreatment with G-CSF is usually effective, but the dose of G-CSF required to \nnormalize blood neutrophils varies greatly. Ten to thirty percent of severe \ncongenital neutropenia patients evolve to develop acute myeloid leukemia, \nnecessitating careful clinical monitoring.",
"Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized \nby severe neutropenia secondary to a maturational arrest at the level of \npromyelocytes. We treated five patients with SCN with recombinant human \ngranulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 42 days and \nsubsequently, between 1 and 3 months later, with rhG-CSF for 142 days. The \nobjective was to evaluate the safety and ability of these factors to elicit a \nneutrophil response. rhGM-CSF was administered at a dose of 3 to 30 \nmicrograms/kg/d (30 to 60 minutes, intravenously). In all patients, a specific, \ndose-dependent increase in the absolute granulocyte counts was observed. \nHowever, in four patients this increase was due to an increase in eosinophils, \nand in only one patient it was due to an increase in the absolute neutrophil \ncounts (ANC). Subsequently, all patients received rhG-CSF at a dose of 3 to 15 \nmicrograms/kg/d subcutaneously. In contrast to rhGM-CSF treatment, all five \npatients responded to rhG-CSF during the first 6 weeks of treatment with an \nincrease in the ANC to above 1,000/microL. The level of ANC could be maintained \nduring maintenance treatment. In one patient, the increase in ANC was associated \nwith an improvement of a severe pneumonitis caused by Peptostreptococcus and \nresistant to antibiotic treatment. No severe bacterial infections occurred in \nany of the patients during CSF treatment. All patients tolerated rhGM-CSF and \nrhG-CSF treatment without severe side effects. These results demonstrate the \nbeneficial effect of rhG-CSF in SCN patients.",
"Severe congenital neutropenia (CN) includes a variety of hematologic disorders \ncharacterized by severe neutropenia, with absolute neutrophil counts (ANC) below \n0.5 x 10(9)/L, and associated with severe systemic bacterial infections from \nearly infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive \ndisorder, characterized histopathologically by early-stage maturation arrest of \nmyeloid differentiation. CN with similar clinical features occurs as an \nautosomal dominant disorder and many sporadic cases also have been reported. \nThis genetic heterogeneity suggests that several pathophysiological mechanisms \nmay lead to this common clinical phenotype. Recent studies on the genetic bases \nof CN have detected inherited or spontaneous point mutations in the neutrophil \nelastase gene (ELA 2) in about 60% to 80% of patients and, less commonly, \nmutations in other genes. Acquisition of additional genetic defects during the \ncourse of the disease, for example, granulocyte colony-stimulating factor \n(G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an \nunderlying genetic instability as a common feature for all congenital \nneutropenia subtypes. Data on more than 600 patients with CN collected by the \nSevere Chronic Neutropenia International Registry (SCNIR) demonstrate that, \nregardless of the particular CN subtype, more than 95% of these patients respond \nto recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x \n10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant \ntransformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment \nimpacts on these adverse events is not fully understood. In recent analyses the \ninfluence of the G-CSF dose required to achieve neutrophil response (ANC \n>1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been \nreported. Hematopoietic stem cell transplantation (HSCT) is still the only \ntreatment available for patients who are refractory to G-CSF treatment."
] | ['http://www.disease-ontology.org/api/metadata/DOID:0050590'] |
5880b583c872c95565000005 | [
22941121,
21547994,
26159652,
22511269,
25983143,
23995725,
25583761,
21796086,
22075415,
27639738
] | train | Which treatment methods were compared in the EXCEL Trial? | list | EXCEL trial compared Everolimus Eluting Stent vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization. | ['Everolimus Eluting Stent', 'Coronary Artery Bypass Surgery'] | [
"PURPOSE OF REVIEW: The aim of this article is to review the current \nrevascularization strategies in patients presenting with unprotected left main \ncoronary artery disease (LMCAD).\nRECENT FINDINGS: Coronary artery bypass grafting (CABG) is the current standard \nof treatment for patients with LMCAD. The development and refinement of \ntechniques increased the number of percutaneous coronary interventions (PCI) in \nLMCAD patients.\nSUMMARY: Although several observational studies show comparable results of CABG \nand/or PCI in patients with LMCAD, there is currently no convincing randomized \nevidence that either one of the two is associated with better long-term \nsurvival. Recent meta-analyses of four small randomized trials revealed a \nsimilar rate of 1-year major adverse cardiovascular and cerebrovascular events, \nhigher rates of target vessel revascularization and lower stroke rates for PCI. \nPooling randomized patients studies stratified by lesion complexity strengthened \nthe hypothesis that CABG is better in more complex LMCAD patients. However, the \nrandomized comparisons are affected by methodological limitations and lack power \nto be conclusive. The ongoing Evaluation of XIENCE V Everolimus Eluting Stent \nSystem Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main \nRevascularization (EXCEL) trial is expected to provide a better answer on the \noptimal treatment strategy for LMCAD patients. In the meantime, risk models need \nto be improved and the most appropriate revascularization strategy for the \nindividual LMCAD patient should be chosen using a multidisciplinary heart team \nthat considers not only risk models but also other clinical and economic facets.",
"OBJECTIVES: The aim of this study is to verify the study hypothesis of the EXCEL \ntrial by comparing percutaneous coronary intervention (PCI) and coronary artery \nbypass graft (CABG) in an EXCEL-like population of patients.\nBACKGROUND: The upcoming EXCEL trial will test the hypothesis that left main \npatients with SYNTAX score ≤ 32 experience similar rates of 3-year death, \nmyocardial infarction (MI), or cerebrovascular accidents (CVA) following \nrevascularization by PCI or CABG.\nMETHODS: We compared the 3-year rates of death/MI/CVA and death/MI/CVA/target \nvessel revascularization (MACCE) in 556 patients with left main disease and \nSYNTAX score ≤ 32 undergoing PCI (n = 285) or CABG (n = 271). To account for \nconfounders, outcome parameters underwent extensive statistical adjustment.\nRESULTS: The unadjusted incidence of death/MI/CVA was similar between PCI and \nCABG (12.7% vs. 8.4%, P = 0.892), while MACCE were higher in the PCI group \ncompared to the CABG group (27.0% vs. 11.8%, P < 0.001). After propensity score \nmatching, PCI was not associated with a significant increase in the rate of \ndeath/MI/CVA (11.8% vs. 10.7%, P = 0.948), while MACCE were more frequently \nnoted among patients treated with PCI (28.8% vs. 14.1%, P = 0.002). Adjustment \nby means of SYNTAX score and EUROSCORE, covariates with and without propensity \nscore, and propensity score alone did not change significantly these findings.\nCONCLUSIONS: In an EXCEL-like cohort of patients with left main disease, there \nseems to be a clinical equipoise between PCI and CABG in terms of death/MI/CVA. \nHowever, even in patients with SYNTAX score ≤ 32, CABG is superior to PCI when \ntarget vessel revascularization is included in the combined endpoint.",
"Percutaneous coronary intervention (PCI) using drug-eluting stents (DES) is \ncurrently considered as a viable alternative to coronary artery bypass graft \nsurgery (CABG) for selected patients with left main coronary artery disease. The \nupdated results of the landmark randomized trials comparing CABG versus PCI \ndemonstrated comparable 5-year outcomes and are in line with the current \nguidelines that designate PCI as a reasonable treatment in this disease subset. \nGiven that the completed randomized trials did not include contemporary DESs, \nthe upcoming results of the ongoing trials evaluating the performance of \nnew-generation DES compared with CABG (such as the EXCEL trial), may further \nhelp to clarify the current role and future recommendations of PCI for left main \ncoronary artery disease. Apart from the recent stent technology, further \nimprovements in outcomes after PCI may be possible when it is used with an \nintegrated approach that combines functional concepts for decision-making, \nadjunctive imaging support and optimal pharmacotherapies.",
"Refinement of interventional techniques, adjunctive pharmacological therapy, and \nthe introduction of drug eluting stents have fostered new interest for the \npercutaneous treatment of unprotected left main coronary artery (ULMCA) \nstenosis. Several observational registries, some randomized controlled trials \nand several meta-analyses have consistently shown no difference in mortality and \nmyocardial infarction between percutaneous coronary intervention (PCI) and \ncoronary artery bypass graft (CABG) surgery in patients with ULMCA stenosis, but \na higher rate of target vessel revascularization in patients treated with PCI. \nAs a consequence, PCI of ULMCA stenosis has been upgraded to class IIa or IIb \nindication in the current European or American College of Cardiology/American \nHeart Association practice guidelines. Although these results are promising, \nthey do not still represent enough evidence for extending PCI of ULMCA stenosis \nto current clinical practice. The EXCEL trial will address the value of PCI in \nrelation to CABG for the treatment of ULMCA stenosis in more than 2000 patients. \nA major breakthrough of the SYNTAX trial has been the demonstration of an \ninteraction between the coronary complexity and the revascularization strategy, \nsuggesting that optimal risk stratification is a key element when deciding the \nbest strategy of revascularization in this high-risk group of patients. \nMultidisciplinary team approach remains essential to provide a balanced \ninformation to the patient and to offer the beast treatment option.",
"Unprotected left main coronary artery (ULMCA) stenosis has relatively high \nprevalence and exposes patients to a high risk for adverse cardiovascular \nevents. The optimal revascularisation strategy (coronary artery bypass surgery \n[CABG] or percutaneous coronary intervention [PCI]) for patients with complex \ncoronary artery disease is a topic of continuing debate. The introduction of the \nnewer-generation drug-eluting stents (DES) -with documented improvements in both \nsafety and efficacy- has prompted the interventional community to design two new \ndedicated randomised trials comparing CABG and PCI: the NOBLE (Coronary Artery \nBypass Grafting Vs Drug Eluting Stent Percutaneous Coronary Angioplasty in the \nTreatment of Unprotected Left Main Stenosis) and EXCEL (Evaluation of XIENCE \nEverolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness \nof Left Main Revascularization) trials. The aims of the present review are to \ndescribe the similarities and contrasts between these two trials as well to \nexplore their future implications in ULMCA treatment.",
"Unprotected left main coronary artery (ULMCA) disease is seen in 4% of patients \nwho undergo angiography. Though coronary artery bypass graft surgery has \ntraditionally been the preferred approach to revascularization, recent major \nsociety guidelines support the use of percutaneous coronary intervention (PCI) \nin properly selected patients. This article provides an overview of recent \nstudies evaluating the efficacy of ULMCA PCI and looking at contemporary \napproaches to the evaluation and percutaneous treatment of ULMCA disease. The \nongoing EXCEL trial will help elucidate the role of ULMCA PCI in the treatment \nof left main disease compared with coronary artery bypass graft surgery.",
"AIMS: To prospectively validate the SYNTAX Score II and forecast the outcomes of \nthe randomized Evaluation of the Xience Everolimus-Eluting Stent Versus Coronary \nArtery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) \nTrial.\nMETHODS AND RESULTS: Evaluation of the Xience Everolimus Eluting Stent vs. \nCoronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization \nis a prospective, randomized multicenter trial designed to establish the \nefficacy and safety of percutaneous coronary intervention (PCI) with the \neverolimus-eluting stent compared with coronary artery bypass graft (CABG) \nsurgery in subjects with unprotected left-main coronary artery (ULMCA) disease \nand low-intermediate anatomical SYNTAX scores (<33). After completion of patient \nrecruitment in EXCEL, the SYNTAX Score II was prospectively applied to predict \n4-year mortality in the CABG and PCI arms. The 95% prediction intervals (PIs) \nfor mortality were computed using simulation with bootstrap resampling (10 000 \ntimes). For the entire study cohort, the 4-year predicted mortalities were 8.5 \nand 10.5% in the PCI and CABG arms, respectively [odds ratios (OR) 0.79; 95% PI \n0.43-1.50). In subjects with low (≤22) anatomical SYNTAX scores, the predicted \nOR was 0.69 (95% PI 0.34-1.45); in intermediate anatomical SYNTAX scores \n(23-32), the predicted OR was 0.93 (95% PI 0.53-1.62). Based on 4-year mortality \npredictions in EXCEL, clinical characteristics shifted long-term mortality \npredictions either in favour of PCI (older age, male gender and COPD) or CABG \n(younger age, lower creatinine clearance, female gender, reduced left \nventricular ejection fraction).\nCONCLUSION: The SYNTAX Score II indicates at least an equipoise for long-term \nmortality between CABG and PCI in subjects with ULMCA disease up to an \nintermediate anatomical complexity. Both anatomical and clinical characteristics \nhad a clear impact on long-term mortality predictions and decision making \nbetween CABG and PCI.",
"Coronary artery bypass grafting (CABG) is the gold standard for the treatment of \nleft main disease, whereas percutaneous coronary intervention is a viable option \nfor patients who are candidates for revascularization but ineligible for CABG. \nCABG is limited by extended hospital stay followed by rehabilitation and \nmediocre long-term patency of saphenous vein grafts. Drug-eluting stents \ndecrease the restenosis rates compared with bare metal stents and provide \ncomparable clinical outcomes with those of CABG. Patients with isolated left \nmain disease limited to the ostium or midbody are most likely to have good \nclinical outcomes with low restenosis and stent thrombosis rates. The results of \nthe ongoing EXCEL trial, which compares left main percutaneous coronary \nintervention with drug-eluting stents and CABG, will provide insight regarding \nthe ideal revascularization strategy for these patients.",
"The Evaluation of Xience Prime or Xience V versus Coronary Artery Bypass Surgery \nfor Effectiveness of Left Main Revascularization (EXCEL) trial is a multicenter, \nongoing trial conducted in patients with left main disease and SYNTAX score ≤ 32 \nto establish the presumptive advantage of percutaneous coronary intervention \n(PCI) versus bypass surgery in patients with less complex coronary artery \ndisease than those enrolled in the Synergy between PCI with Taxus and Cardiac \nSurgery (SYNTAX) trial. In this article, we aimed at critically discussing key \nfeatures and issues relevant to design and clinical interpretation of this new \ncontemporary trial of left main PCI.",
"AIMS: Coronary artery bypass graft (CABG) surgery is the standard of care for \nrevascularisation of patients with left main coronary artery disease (LMCAD). \nRecent studies have suggested that percutaneous coronary intervention (PCI) with \ndrug-eluting stents (DES) may provide comparable outcomes in selected patients \nwith LMCAD without extensive CAD. We therefore designed a trial to investigate \nwhether PCI with XIENCE cobalt-chromium everolimus-eluting stents (CoCr-EES) \nwould result in non-inferior or superior clinical outcomes to CABG in selected \npatients with LMCAD.\nMETHODS AND RESULTS: The Evaluation of XIENCE versus Coronary Artery Bypass \nSurgery for Effectiveness of Left Main Revascularization (EXCEL) trial is a \nprospective, open-label, multicentre, international study of 1,900 randomised \nsubjects. Patients with significant LMCAD with a SYNTAX score ≤32 and local \nHeart Team consensus that the subject is appropriate for revascularisation by \nboth PCI and CABG are consented and randomised 1:1 to undergo PCI using CoCr-EES \nor CABG. All patients undergo follow-up for five years. The primary endpoint is \nthe three-year composite rate of death, stroke or myocardial infarction, \nassessed at a median follow-up of at least three years (with at least two-year \nfollow-up in all patients), powered for sequential non-inferiority and \nsuperiority testing.\nCONCLUSIONS: The EXCEL study will define the contemporary roles of CABG and PCI \nusing XIENCE CoCr-EES in patients with LMCAD disease with low and intermediate \nSYNTAX scores."
] | ['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D017428', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002986', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D017326', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016430'] |
6027505c1cb411341a0000e6 | [
28412960,
32558178,
32901611,
32622397
] | train | Which treatments were compared in the UNBLOCS trial? | list | The UNBLOCS trial compared thulium laser transurethral vaporesection of the prostate versus transurethral resection of the prostate for men with lower urinary tract symptoms or urinary retention. | ['thulium laser transurethral vaporesection of the prostate', 'transurethral resection of the prostate'] | [
"BACKGROUND: Transurethral resection of the prostate (TURP) has been the standard \noperation for benign prostatic obstruction (BPO) for 40 years, with \napproximately 25,000 procedures performed annually, and has remained largely \nunchanged. It is generally a successful operation, but has well-documented risks \nfor the patient. Thulium laser transurethral vaporesection of the prostate \n(ThuVARP) vaporises and resects the prostate using a surgical technique similar \nto TURP. The small amount of study data currently available suggests that \nThuVARP may have certain advantages over TURP, including reduced blood loss and \nshorter hospital stay, earlier return to normal activities, and shorter duration \nof catheterisation.\nDESIGN: A multicentre, pragmatic, randomised, controlled, parallel-group trial \nof ThuVARP versus standard TURP in men with BPO. Four hundred and ten men \nsuitable for prostate surgery were randomised to receive either ThuVARP or TURP \nat four university teaching hospitals, and three district general hospitals. The \nkey aim of the trial is to determine whether ThuVARP is equivalent to TURP \njudged on both the patient-reported International Prostate Symptom Score (IPSS) \nand the maximum urine flow rate (Qmax) at 12 months post-surgery.\nDISCUSSION: The general population has an increased life expectancy. As men get \nolder their prostates enlarge, potentially causing BPO, which often requires \nsurgery. Therefore, as the population ages, more prostate operations are needed \nto relieve obstruction. There is hence sustained interest in the condition and \nincreasing need to find safer techniques than TURP. Various laser techniques \nhave become available but none are widely used in the NHS because of lengthy \ntraining required for surgeons or inferior performance on clinical outcomes. \nPromising initial evidence from one RCT shows that ThuVARP has equivalent \nclinical effectiveness when compared to TURP, as well as other potential \nadvantages. As ThuVARP uses a technique similar to that used in TURP, the \nlearning curve is short, potentially making it also very quickly generalisable. \nThis randomised study is designed to provide the high-quality evidence, in an \nNHS setting, with a range of patient-reported, clinical and cost-effectiveness \noutcomes, which will underpin and inform future NICE guidance.\nTRIAL REGISTRATION: ISRCTN registry, ISRCTN00788389 . Registered on 20 September \n2013.",
"OBJECTIVE: To determine the cost-effectiveness of the current 'gold standard' \noperation of transurethral resection of the prostate (TURP) compared to the new \nlaser technique of thulium laser transurethral vaporesection of the prostate \n(ThuVARP) in men with benign prostatic obstruction (BPO) within the UK National \nHealth Service (NHS).\nPATIENTS AND METHODS: The trial was conducted across seven UK centres (four \nuniversity teaching hospitals and three district general hospitals). A total of \n410 men aged ≥18 years presenting with either bothersome lower urinary tract \nsymptoms (LUTS) or urinary retention secondary to BPO, and suitable for surgery, \nwere randomised (whilst under anaesthetic) 1:1 to receive the TURP or ThuVARP \nprocedure. Resource use in relation to the operation, initial inpatient stay, \nand subsequent use of NHS services was collected for 12 months from \nrandomisation (equivalent to primary effectiveness outcome) using hospital \nrecords and patient questionnaires. Resources were valued using UK reference \ncosts. Quality adjusted life years (QALYs) were calculated from the EuroQoL five \nDimensions five Levels (EQ-5D-5L) questionnaire completed at baseline, 3- and \n12-months. Total adjusted mean costs, QALYs and incremental Net Monetary Benefit \nstatistics were calculated: cost-effectiveness acceptability curves and \nsensitivity analyses addressed uncertainty.\nRESULTS: The total adjusted mean secondary care cost over the 12 months in the \nTURP arm (£4244) was £9 (95% CI -£376, £359) lower than the ThuVARP arm (£4253). \nThe ThuVARP operation took on average 21 min longer than TURP. The adjusted mean \ndifference of QALYs (0.01 favouring TURP, 95% CI -0.01, 0.04) was similar \nbetween the arms. There is a 76% probability that TURP is the cost-effective \noption compared with ThuVARP at the £20 000 per QALY willingness to pay \nthreshold used by National Institute for Health and Care Excellence (NICE).\nCONCLUSION: One of the anticipated benefits of the laser surgery, reduced length \nof hospital stay with an associated reduction in cost, did not materialise \nwithin the study. The longer duration of the ThuVARP procedure is important to \nconsider, both from a patient perspective in terms of increased time under \nanaesthetic, and from a service delivery perspective. TURP remains a highly \ncost-effective treatment for men with BPO.",
"BACKGROUND: Transurethral resection of the prostate (TURP) is the standard \noperation for benign prostatic obstruction (BPO). Thulium laser transurethral \nvaporesection of the prostate (ThuVARP) vaporises and resects the prostate using \na technique similar to TURP. The small amount of existing literature suggests \nthat there may be potential advantages of ThuVARP over TURP.\nOBJECTIVE: To determine whether or not the outcomes from ThuVARP are equivalent \nto the outcomes from TURP in men with BPO treated in the NHS.\nDESIGN: A multicentre, pragmatic, randomised controlled parallel-group trial, \nwith an embedded qualitative study and economic evaluation.\nSETTING: Seven UK centres - four university teaching hospitals and three \ndistrict general hospitals.\nPARTICIPANTS: Men aged ≥ 18 years who were suitable to undergo TURP, presenting \nwith bothersome lower urinary tract symptoms (LUTS) or urinary retention \nsecondary to BPO.\nINTERVENTIONS: Patients were randomised 1 : 1 to receive TURP or ThuVARP and \nremained blinded.\nMAIN OUTCOME MEASURES: Two co-primary outcomes - patient-reported International \nProstate Symptom Score (IPSS) and clinical measure of maximum urine flow rate \n(Qmax) at 12 months post surgery.\nRESULTS: In total, 410 men were randomised, 205 to each arm. The two procedures \nwere equivalent in terms of IPSS [adjusted mean difference 0.28 points higher \nfor ThuVARP (favouring TURP), 95% confidence interval (CI) -0.92 to 1.49 \npoints]. The two procedures were not equivalent in terms of Qmax (adjusted mean \ndifference 3.12 ml/second in favour of TURP, 95% CI 0.45 to 5.79 ml/second), \nwith TURP deemed superior. Surgical outcomes, such as complications and blood \ntransfusion rates, and hospital stay were similar for both procedures. \nPatient-reported urinary and sexual symptoms were also similar between the arms. \nQualitative interviews indicated similar patient experiences with both \nprocedures. However, 25% of participants in the ThuVARP arm did not undergo \ntheir randomised allocation, compared with 2% of participants in the TURP arm. \nProstate cancer was also detected less frequently from routine histology after \nThuVARP (65% lower odds of detection) in an exploratory analysis. The adjusted \nmean differences between the arms were similar for secondary care NHS costs (£9 \nhigher for ThuVARP, 95% CI -£359 to £376) and quality-adjusted life-years (0.01 \nfavouring TURP, 95% CI -0.04 to 0.01).\nLIMITATIONS: Complications were recorded in prespecified categories; those not \nprespecified were excluded owing to variable reporting. Preoperative Qmax and \nIPSS data could not be collected for participants with indwelling catheters, \nmaking adjustment for baseline status difficult.\nCONCLUSIONS: TURP was superior to ThuVARP in terms of Qmax, although both \noperations resulted in a Qmax considered clinically successful. ThuVARP also \npotentially resulted in lower detection rates of prostate cancer as a result of \nthe smaller volume of tissue available for histology. Length of hospital stay \nafter ThuVARP, anticipated to be a key benefit, was equal to that after TURP in \nthis trial. Overall, both ThuVARP and TURP were effective procedures for BPO, \nwith minor benefits in favour of TURP. Therefore, the results suggest that it \nmay be appropriate that new treatment alternatives continue to be compared with \nTURP.\nFUTURE WORK: Longer-term follow-up to assess reoperation rates over time, and \nresearch into the comparative effectiveness of ThuVARP and TURP in large \nprostates.\nTRIAL REGISTRATION: Current Controlled Trials ISRCTN00788389.\nFUNDING: This project was funded by the National Institute for Health Research \n(NIHR) Health Technology Assessment programme and will be published in full in \nHealth Technology Assessment; Vol. 24, No. 41. See the NIHR Journals Library \nwebsite for further project information.",
"BACKGROUND: Transurethral resection of the prostate (TURP) is the standard \noperation for benign prostatic obstruction. Thulium laser transurethral \nvaporesection of the prostate (ThuVARP) is a technique with suggested advantages \nover TURP, including reduced complications and hospital stay. We aimed to \ninvestigate TURP versus ThuVARP in men with lower urinary tract symptoms or \nurinary retention secondary to benign prostatic obstruction.\nMETHODS: In this randomised, blinded, parallel-group, pragmatic equivalence \ntrial, men in seven UK hospitals with bothersome lower urinary tract symptoms or \nurinary retention secondary to benign prostatic obstruction were randomly \nassigned (1:1) at the point of surgery to receive ThuVARP or TURP. Patients were \nmasked until follow-up completion. Centres used their usual TURP procedure \n(monopolar or bipolar). All trial surgeons underwent training on the ThuVARP \ntechnique. Co-primary outcomes were maximum urinary flow rate (Qmax) and \nInternational Prostate Symptom Score (IPSS) at 12-months post-surgery. \nEquivalence was defined as a difference of 2·5 points or less for IPSS and 4 mL \nper s or less for Qmax. Analysis was done according to the intention-to-treat \nprinciple. The trial is registered with the ISRCTN Registry, ISRCTN00788389.\nFINDINGS: Between July 23, 2014, and Dec 30, 2016, 410 men were randomly \nassigned to ThuVARP or TURP, 205 per study group. TURP was superior for Qmax \n(mean 23·2 mL per s for TURP and 20·2 mL per s for ThuVARP; adjusted difference \nin means -3·12, 95% CI -5·79 to -0·45). Equivalence was shown for IPSS (mean 6·3 \nfor TURP and 6·4 for ThuVARP; adjusted difference in means 0·28, -0·92 to 1·49). \nMean hospital stay was 48 h in both study groups. 91 (45%) of 204 patients in \nthe TURP group and 96 (47%) of 203 patients in the ThuVARP group had at least \none complication.\nINTERPRETATION: TURP and ThuVARP were equivalent for urinary symptom improvement \n(IPSS) 12-months post-surgery, and TURP was superior for Qmax. Anticipated laser \nbenefits for ThuVARP of reduced hospital stay and complications were not \nobserved.\nFUNDING: UK National Institute for Health Research Health Technology Assessment \nProgramme."
] | nan |
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20935678,
18794879
] | train | Which tumor suppressor is referred to as "the guardian of the genome"? | factoid | The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. It plays a crucial role in regulating the transcription of numerous genes responsible for cells cycle arrest, DNA repair, angiogenesis, cell senescence, or apoptosis in response to various stress signals, and is considered one of the most important players in the development of cancer. p53 contributes to the maintenance of genomic stability. Thus, p53 has been described as "the guardian of the genome". | 5 | [
"Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell \ncycle, ensuring correct chromosome segregation and normal progression through \nmitosis. Aurora B is overexpressed in many types of human cancers, which has \nmade it an attractive target for cancer therapies. Tumor suppressor p53 is a \ngenome guardian and important negative regulator of the cell cycle. Whether \nAurora B and p53 are coordinately regulated during the cell cycle is not known. \nWe report that Aurora B directly interacts with p53 at different subcellular \nlocalizations and during different phases of the cell cycle (for instance, at \nthe nucleus in interphase and the centromeres in prometaphase of mitosis). We \nshow that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the \ndegradation of p53 through the polyubiquitination-proteasome pathway, thus \nfunctionally suppressing the expression of p53 target genes involved in cell \ncycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic inhibition of \nAurora B in cancer cells with WT p53 increased p53 protein level and expression \nof p53 target genes to inhibit tumor growth. Together, these results define a \nmechanism of p53 inactivation during the cell cycle and imply that oncogenic \nhyperactivation or overexpression of Aurora B may compromise the tumor \nsuppressor function of p53. We have elucidated the antineoplastic mechanism for \nAurora B kinase inhibitors in cancer cells with WT p53.",
"The classical functions of p53 protein are those related to its role on DNA \ndamage, cell growth arrest, senescence and apoptosis. For this reason it is \ncalled 'the guardian of the genome' and is considered one of the most important \nplayers in the development of cancer. However, more recently it has been show \nthat p53 is not only involved in cancer, but also in ageing. p53 is stimulated \nby stress, which in turn results in the activation of a wide range of \ntranscriptional targets. Low-intensity stress will activate p53 in a manner \nwhich results in antioxidant response, thus protecting against ageing because of \nits antioxidant function. On the contrary, high-intensity activation of p53 will \nresult in an increase of oxidative stress by activation of p53-mediated \npro-oxidant targets, thus increasing the rate of ageing, but protecting against \ncancer.",
"The tumor-suppressor p53 is a multifunctional protein mainly responsible for \nmaintaining genomic integrity. p53 induces its tumor-suppressor activity by \neither causing cell-cycle arrest (G(1)/S or G(2)/M) or inducing cells to undergo \napoptosis. This function of wild-type p53 as \"guardian of the genome\" is \npresumably achieved by forming molecular complexes with different DNA targets as \nwell as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45, \np21, 14-3-3sigma, Bax and Apaf-1. Upon activation, p53 activates p21, which in \nturn controls the cell cycle by regulating G(1) or G(2) checkpoints. Here, we \nreport SMAR1 as one such p53-interacting protein that is involved in delaying \ntumor progression in vivo as well as in regulating the cell cycle. SMAR1 is a \nnewly identified MARBP involved in chromatin-mediated gene regulation. The SMAR1 \ngene encodes at least 2 alternatively spliced variants: SMAR1(L) (the \nfull-length form) and SMAR1(S) (the shorter form). We report that expression of \nSMAR1(S), but not of SMAR1(L), mRNA was decreased in most of the human cell \nlines examined, suggesting selective silencing of SMAR1(S). Overexpression of \nSMAR1(S) in mouse melanoma cells (B16F1) and their subsequent injection in \nC57BL/6 mice delays tumor growth. Exogenous SMAR1(S) causes significant \nretardation of B16F1 cells in the G(2)/M phase of the cell cycle compared to \nSMAR1(L). SMAR1(S) activates p53-mediated reporter gene expression in mouse \nmelanoma cells, breast cancer cells (MCF-7) and p53 null cells (K562), followed \nby activation of its downstream effector, p21. We further demonstrate that SMAR1 \nphysically interacts and colocalizes with p53. These data together suggest that \nSMAR1 is the only known MARBP that delays tumor progression via direct \nactivation and interaction with tumor-suppressor p53.",
"Mutation of p53 occurs in 15 to 20% of all breast cancers, and with higher \nfrequency in estrogen-receptor negative and high-grade tumors. Certain p53 \nmutations contribute to malignant transformation not only through loss of \nwild-type p53 but also through a gain of function of specific p53 mutations. How \nthese hotspot mutations turn p53 from a tumor suppressor into an oncogene had \nuntil now remained incompletely understood. In an elegant paper published in the \nJuly 12 issue of Cancer Cell, Girardini and colleagues show how Pin1-mediated \nprolyl isomerization, a regulatory mechanism intended by evolution to support \np53's function as a guardian of the genome, can go haywire and accelerate \nmalignant transformation when p53 carries a dominant-negative mutation.",
"The tumor suppressor protein p53 has been described \"as the guardian of the \ngenome\" for its crucial role in regulating the transcription of numerous genes \nresponsible for cells cycle arrest, senescence, or apoptosis in response to \nvarious stress signals. Although p53 promotes longevity by decreasing the risk \nof cancer through activation of apoptosis or cellular senescence, several \nfindings suggest that an increase of its activity may have deleterious effects \nleading to selected aspects of the aging phenotype and neurodegenerative \ndiseases. There is the link between p53 and oxidative stress, the latter a \ncrucial factor that contributes to neurodegenerative processes like Alzheimer \ndisease (AD). In the present study, using a proteomics approach, we analyzed the \nimpact of lack of p53 on the expression of several brain mitochondrial proteins \ninvolved in different pathways, and how lack of p53 may present a target to \nrestore neuronal impairments. Our investigation on isolated brain mitochondria \nfrom p53((-/-)) mice also provides a better understanding of the \np53-mitochondria relationship and its involvement in the development of many \ndiseases.",
"Various stresses and DNA-damaging agents trigger transcriptional activity of p53 \nby post-translational modifications, making it a global regulatory switch that \ncontrols cell proliferation and apoptosis. Earlier we have shown that the novel \nMAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal \ndomain of SMAR1 (the arginine-serine-rich domain) that is phosphorylated by \nprotein kinase C family proteins and is responsible for p53 interaction, \nactivation, and stabilization within the nucleus. SMAR1-mediated stabilization \nof p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also \ndemonstrate that this arginine-serine (RS)-rich domain triggers the various cell \ncycle modulating proteins that decide cell fate. Furthermore, phenotypic \nknock-down experiments using small interfering RNA showed that SMAR1 is required \nfor activation and nuclear retention of p53. The level of phosphorylated p53 was \nsignificantly increased in the thymus of SMAR1 transgenic mice, showing in vivo \nsignificance of SMAR1 expression. This is the first report that demonstrates the \nmechanism of action of the MAR-binding protein SMAR1 in modulating the activity \nof p53, often referred to as the \"guardian of the genome.\"",
"Side effects of chemotherapy are a major impediment in the treatment of cancer. \nCyclotherapy is an emerging therapeutic strategy for protecting normal cells \nfrom the side effects of chemotherapy. Low, non-genotoxic doses of known p53 \nactivators can be used to induce p53-dependent cell cycle arrest in normal cells \nbearing wild-type p53. This cytostatic effect of p53 can protect normal cells \nfrom the toxicity of S- or M-phase poisons. Here, we have reviewed existing \ncyclotherapy regimens using two well-known p53 activators, nutlin-3 and \nactinomycin D. We have highlighted an exemplar clinical perspective for \ncyclotherapy in breast cancer. The recent development of novel stapled peptides \nas activators of p53 without the corresponding cytotoxicity holds great promise \nfor cyclotherapy to enhance the therapeutic window of existing chemotherapy \ndrugs.",
"The p53 guardian of the genome is inactivated in the majority of cancers, mostly \nthrough missense mutations that cause single residue changes in the DNA binding \ncore domain of the protein. Not only do such mutations result in the abrogation \nof wild-type p53 activity, but the expressed p53 mutant proteins also tend to \ngain oncogenic functions, such as interference with wild-type p53-independent \napoptosis. Because p53 mutants are highly expressed in cancer cells and not in \nnormal cells, their reactivation to wild-type p53 function may eliminate the \ncancer by apoptosis or another p53-dependent mechanism. Several studies that \nembarked on this quest for reactivation have succeeded in restoring wildtype p53 \nactivity to several p53 mutants. However, mutants with more extensive structural \nchanges in the DNA binding core domain may be refractory to reactivation to the \nwild-type p53 phenotype. Therefore, understanding the structure and functions of \noncogenic p53 mutants may lead to more potent reactivation modalities or to the \nability to eliminate mutant p53 gain of function.",
"Tumor development in the skin may be a multistep process where multiple genetic \nalterations occur successively. The p53 gene is involved in genome stability and \nthus is referred to as \"the guardian of the genome.\" To better understand the \nantigenotoxic effects of p53 in ultraviolet light B (UVB)-induced mutagenesis, \nmutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) \ngpt delta mice. In the mouse model, point mutations and deletions are separately \nidentified by the gpt and Spi(-) assays, respectively. The mice were exposed to \nUVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2) . The mutant frequencies (MFs) \nwere determined 4 weeks after the irradiation. All doses of UVB irradiation \nenhanced gpt MFs by about 10 times than that of unirradiated mice. There were no \nsignificant differences in gpt MFs and the mutation spectra between p53(+/+) and \np53(-/-) mice. The predominant mutations induced by UVB irradiation were G:C to \nA:T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, \nthe frequencies of Spi(-) large deletions of more than 1 kb and complex-type \ndeletions with rearrangements were significantly higher than those of the Spi(-) \nlarge deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency \nof more than 1 kb deletions and complex types increased in a dose-dependent \nmanner in the p53(+/+) mice. However, no increase of such large deletions was \nobserved in irradiated p53(-/-) mice. These results suggest that the \nantigenotoxic effects of p53 may be specific to deletions and complex-type \nmutations induced by double-strand breaks in DNA.",
"The tumor suppressor protein, p53, is often referred to as the guardian of the \ngenome. When p53 function is impaired, its ability to preserve genomic integrity \nis compromised. This may result in an increase in mutation on both a molecular \nand chromosomal level and contribute to the progression to a malignant \nphenotype. In order to study the effect of p53 function on the acquisition of \nmutation, in vitro and in vivo models have been developed in which both the \nfrequency and mechanism of mutation can be analyzed. In human lymphoblastoid \ncells in which p53 function was impaired, both the spontaneous and induced \nmutant frequency increased at the autosomal thymidine kinase (TK) locus. The \nmutant frequency increased to a greater extent in cell lines in which p53 \nharbored a point mutation than in those lines in which a \"null\" mutation had \nbeen introduced by molecular targeting or by viral degradation indicating a \npossible \"gain-of-function\" associated with the mutant protein. Further, \nmolecular analysis revealed that the loss of p53 function was associated with a \ngreater tendency towards loss-of-heterozygosity (LOH) within the TK gene that \nwas due to non-homologous recombination than that found in wild-type cells. Most \ndata obtained from the in vivo models uses the LacI reporter gene that does not \nefficiently detect mutation that results in LOH. However, studies that have \nexamined the effect of p53 status on mutation in the adenine phosphoribosyl \ntransferase (APRT) gene in transgenic mice also suggest that loss of p53 \nfunction results in an increase in mutation resulting from non-homologous \nrecombination. The results of these studies provide clear and convincing \nevidence that p53 plays a role in modulating the mutant frequency and the \nmechanism of mutation. In addition, the types of mutation that occur within the \np53 gene are also of importance in determining the mutant frequency and the \npathways leading to mutation.",
"The process of malignant transformation universally entails genetic damage and \noncogenic signaling, two stresses that are signaled to p53 through different \ngenetic pathways. Based on this, it is possible to distinguish two jobs for p53: \n\"guardian of the genome\" that consists in sensing and reacting to DNA damage \nthrough the ATM/ATR and Chk1/Chk2 kinases, and \"policeman of the oncogenes\" \nthat, correspondingly, consists in responding to oncogenic signaling through the \np53-stabilizing protein ARF. Contrary to expectation, recent genetic evidence in \nmice indicates that the response of p53 to DNA damage has little or no impact on \ncancer protection. In contrast, ARF-dependent activation of p53 is critical for \np53-mediated tumor suppression. Here, we discuss the mechanistic implications of \nthese observations and their relevance for cancer therapy.",
"The PTEN tumor suppressor protein inhibits phosphatidylinositol 3-kinase \n(PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When \nrestricted to the cytoplasm, Mdm2 is degraded. The ability of PTEN to inhibit \nthe nuclear entry of Mdm2 increases the cellular content and transactivation of \nthe p53 tumor suppressor protein. Retroviral transduction of PTEN into U87MG \n(PTEN null) glioblastoma cells increases p53 activity and expression of p53 \ntarget genes and induces cell cycle arrest. U87MG/PTEN glioblastoma cells are \nmore sensitive than U87MG/PTEN null cells to death induced by etoposide, a \nchemotherapeutic agent that induces DNA damage. Previously, tumor suppressor \nproteins have been supposed to act individually to suppress cancers. Our results \nestablish a direct connection between the activities of two major tumor \nsuppressors and show that they act together to respond to stresses and \nmalignancies. PTEN protects p53 from survival signals, permitting p53 to \nfunction as a guardian of the genome. By virtue of its capacity to protect p53, \nPTEN can sensitize tumor cells to chemotherapy that relies on p53 activity. p53 \ninduces PTEN gene expression, and here it is shown that PTEN protects p53, \nindicating that a positive feedback loop may amplify the cellular response to \nstress, damage, and cancer.",
"The p53 protein is the cell's principal bastion of defense against \ntumor-associated DNA damage. Commonly referred as a \"guardian of the genome\", \np53 is responsible for determining the fate of the cell when the integrity of \nits genome is damaged. The development of tumors requires breaching this defense \nline. All known tumor cells either mutate the p53 gene, or in a similar number \nof cases, use internal cell p53 modulators, Mdm2 and Mdmx proteins, to disable \nits function. The release of functional p53 from the inhibition by Mdm2 and Mdmx \nshould in principle provide an efficient, nongenotoxic means of cancer therapy. \nIn recent years substantial progress has been made in developing novel \np53-activating molecules thanks to several reported crystal structures of Mdm2/x \nin complex with p53-mimicking peptides and nonpeptidic drug candidates. \nUnderstanding the structural attributes of ligand binding holds the key to \ndeveloping novel, highly effective, and selective drug candidates. Two \nlow-molecular-weight compounds have just recently progressed into early clinical \nstudies.",
"During the past ten years, microRNAs (miRNAs) have been shown to play a more \nsignificant role in the formation and progression of cancer diseases than \npreviously thought. With an increase in reports about the dysregulation of \nmiRNAs in diverse tumor types, it becomes more obvious that classic \ntumor-suppressive molecules enter deep into the world of miRNAs. Recently, it \nhas been demonstrated that a typical tumor suppressor p53, known as the guardian \nof the genome, regulates some kinds of miRNAs to contribute to tumor suppression \nby the induction of cell-cycle arrest and apoptosis. Meanwhile, miRNAs \ndirectly/indirectly control the expression level and activity of p53 to \nfine-tune its functions or to render p53 inactive, indicating that the interplay \nbetween p53 and miRNA is overly complicated. The findings, along with current \nstudies, will underline the continuing importance of understanding this \ninterlocking control system for future therapeutic strategies in cancer \ntreatment and prevention.",
"The tumor suppressor p53 is often referred to as \"the guardian of the genome\" \nbecause of its central role in the cellular response to oncogenic stress and \nprevention of tumor development. Mutations of p53 in acute myeloid leukemia \n(AML) are rare but resistance to chemotherapy has been reported because of the \nderegulation of the p53 signaling and differentiation pathways. It is known that \nthe interaction of the vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25D) \nwith its functional vitamin D receptor leads to differentiation, G(1) arrest, \nand increased cell survival in p53-null AML cells. However, there are no reports \non the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we \nexamine vitamin D signaling in AML cells MOLM-13 and OCI-AML3 expressing \nwild-type p53 in the presence and absence of the MDM2 antagonist nutlin-3. We \nfind that 1,25D alone induces monocytic differentiation in these cell lines \nsimilar to that seen in p53-null AML cells, suggesting that the presence of \nwild-type p53 is compatible with activation of vitamin D signaling. Combination \nof nutlin-3a with 1,25D accelerated programmed cell death, likely because of \nenhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and \ndownregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, \nand phosphorylated extracellular signal-regulated kinase 2.",
"p53 has been referred to as the 'guardian of the genome' because of its role in \nprotecting the cell from DNA damage. p53 performs its duties by regulating \ncell-cycle progression and DNA repair and, in cases of irreparable DNA damage, \nby executing programmed cell death. Mitochondria are an important target of \ntranscription-dependent and -independent actions of p53 to carry out the \napoptotic function. However, increasing evidence suggests that p53 activity is \nregulated by mitochondria. Cellular insults that alter mitochondrial function \ncan have important consequences on p53 activity. In light of these new findings, \nthe following review focuses on p53/mitochondria connections, in particular how \nreactive oxygen species generated at mitochondria regulate p53 activity. A \nbetter understanding of the mechanisms by which mitochondria regulate p53 may \nhave an impact on our understanding of the development and progression of many \ndiseases, especially cancer.",
"The TP53 gene, first described in 1979, was identified as a tumor suppressor \ngene in 1989, when it became clear that its product, the p53 nuclear \nphosphoprotein, was frequently inactivated in many different forms of cancers. \nNicknamed \"guardian of the genome\", TP53 occupies a central node in stress \nresponse networks. The p53 protein has a key role as transcription factor in \nlimiting oncogenesis through several growth suppressive functions, such as \ninitiating apoptosis, senescence, or cell cycle arrest. The p53 protein is \ndirectly inactivated in about 50% of all tumors as a result of somatic gene \nmutations or deletions, and over 80% of tumors demonstrate dysfunctional p53 \nsignaling. Beyond the undeniable importance of p53 as a tumor suppressor, an \nincreasing number of new functions for p53 have been reported, including its \nability to regulate energy metabolism, to control autophagy, and to participate \nin various aspects of differentiation and development. Recently, studies on \ngenetic variations in TP53 among different populations have led to the notion \nthat the p53 protein might play an important role in regulating fertility. This \nreview summarizes current knowledge on the basic functions of different genes of \nthe TP53 family and TP53 pathway with respect to fertility. We also provide \noriginal analyses based on genomic and genotype databases, providing further \ninsights into the possible roles of the TP53 pathway in human reproduction.",
"The p53 gene has been referred to as 'the guardian of the genome' because it \ncontrols apoptosis and cell cycle arrest. The purpose of this study was to \nevaluate the association of p53 codon 72 genetic polymorphism and the p53 \nimmunohistochemistry with Helicobacter pylori-associated gastroduodenal \ndiseases, including gastric cancer. This study included 1,852 subjects: controls \nand patients with gastric cancer, dysplasia, benign gastric ulcers, and duodenal \nulcers (DU). Biallelic polymorphism was genotyped by restriction fragment length \npolymorphism. Immunohistochemical analysis for the detection of mutant type p53 \nexpression was performed. The frequency of the Pro/Pro allele of the p53 codon \n72 was higher in the patients with H. pylori-positive dysplasia than in controls \n(OR: 2.3, 95% CI: 1.3-4.3), but it was less frequent among patients with a H. \npylori-positive DU (OR: 0.5, 95% CI: 0.3-0.8). However, there was no significant \nassociation with gastric cancer, including the location, stage, or histological \ntype of gastric cancer. Expression of a mutant type of p53 protein was detected \nin 6.3% of dysplastic tissues and 26.5% of cancerous tissues compared 0% in the \ncontrols. Positive expression was higher in the intestinal type of cancer \n(34.9%) than in the diffuse type (15.0%; P = 0.001). These results suggest that \ngenetic polymorphism of p53 codon 72 played a role in the determination of H. \npylori-associated gastroduodenal diseases, but p53 immunostaining did not \ncorrelate with those of the p53 genetic polymorphism analysis.",
"Carcinogenesis is a multistage process, involving oncogene activation and tumor \nsuppressor gene inactivation as well as complex interactions between tumor and \nhost tissues, leading ultimately to an aggressive metastatic phenotype. Among \nmany genetic lesions, mutational inactivation of p53 tumor suppressor, the \n\"guardian of the genome,\" is the most frequent event found in 50% of human \ncancers. p53 plays a critical role in tumor suppression mainly by inducing \ngrowth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. \nIn addition, p53 generally confers the cancer cell sensitivity to \nchemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven \nanticancer drug discovery. This review will focus on the approaches currently \nundertaken to target p53 and its regulators with an overall goal either to \nactivate p53 in cancer cells for killing or to inactivate p53 temporarily in \nnormal cells for chemoradiation protection. The compounds that activate wild \ntype (wt) p53 would have an application for the treatment of wt p53-containing \nhuman cancer. Likewise, the compounds that change p53 conformation from mutant \nto wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using \na synthetic lethal mechanism can be used to selectively treat human cancer \nharboring a mutant p53. The inhibitors of wt p53 can be used on a temporary \nbasis to reduce the normal cell toxicity derived from p53 activation. Thus, \nsuccessful development of these three classes of p53 modulators, to be used \nalone or in combination with chemoradiation, will revolutionize current \nanticancer therapies and benefit cancer patients.",
"The p53 tumor suppressor protein has long been recognized as the central factor \nprotecting humans from cancer. It has been famously dubbed \"the guardian of the \ngenome\" due to its ability to respond to genotoxic stress, such as DNA damage \nand other stress signals, and to protect the genome by inducing a variety of \nbiological responses including DNA repair, cell cycle arrest, and apoptosis. \nHowever, the tumor suppressive effects of p53 go far beyond its roles in \nmediating these three processes. There is growing evidence that p53 also exerts \nits effects on multiple aspects of tumor formation, including suppression of \nmetastasis and, as summarized in this review, inhibition of new blood vessel \ndevelopment (angiogenesis). The p53 protein has been shown to limit angiogenesis \nby at least three mechanisms: (1) interfering with central regulators of hypoxia \nthat mediate angiogenesis, (2) inhibiting production of proangiogenic factors, \nand (3) directly increasing the production of endogenous angiogenesis \ninhibitors. The combination of these effects allows p53 to efficiently shut down \nthe angiogenic potential of cancer cells. Inactivation of p53, which occurs in \napproximately half of all tumors, reverses these effects; as a consequence, \ntumors carrying p53 mutations appear more vascularized and are often more \naggressive and correlate with poor prognosis for treatment. Thus, the loss of \nfunctional p53 during tumorigenesis likely represents an essential step in the \nswitch to an angiogenic phenotype that is displayed by aggressive tumors.",
"Approximately 50% of sporadic human tumors harbor somatic mutations in the p53 \ngene locus, while germ line mutations confer a high familial risk and are \nassociated with Li-Fraumeni Syndrome patients. The p53 tumor suppressor protein \nis often referred to as the \"guardian of the genome\" since its response to \nDNA-damage or checkpoint failure gives rise to a series of anti-proliferative \nresponses. One of the most important functions of p53 is its ability to induce \napoptosis, while disruption of this route can promote tumor progression and \nchemo resistance. Besides its ability to promote apoptosis through transcription \ndependent mechanisms, p53 may also be able to activate apoptosis independent of \ntranscriptional regulation. Therefore, to ensure normal cell growth, p53 levels \nand activity are tightly regulated. Upon diverse forms of cellular stress the \nsteady state levels and transcriptional activity of p53 are considerably \nincreased. The stabilization and activation of p53 are a result of hindered \ninhibition by its negative regulators, e.g. Mdmx (also known as Mdm4) and Mdm2, \nwhile on the other hand activators such as HIPK2 and DYRK2 enhance the p53 \nresponse. The continually increasing understanding of the mechanisms of \nregulation of p53 may provide the basis for new drug designs that could \neventually lead to therapeutics to reactivate p53 in cancers.",
"Tumor suppressor p53 functions as a \"guardian of the genome\" to prevent cells \nfrom transformation. p53 is constitutively ubiquitinated and degradated in \nunstressed conditions, thereby suppressing the expression. However, cellular \nstimuli enable p53 to escape from the negative regulation, and then stably \nexpressed p53 transactivates its target genes to induce cell cycle arrest, DNA \nrepair, or apoptosis. Promoter preference of target genes is determined by \nmodification status of p53. Because p53 has two critical roles in the decision \nof cell fate, stopping cell cycle to repair damaged DNA or induction of \napoptotic cell death in response to DNA damage, elucidation of switching \nmechanisms on p53 functions is of particular importance. Here we review recent \nevidence how several post-translational modifications of p53 including \nmethylation, phosphorylation, acetylation, and ubiquitination, affect the \nfunctions of p53 in response to cellular stress.",
"Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly \nexpressed in a broad spectrum of tumors and its expression correlates often with \npoor prognosis, suggesting its potential as a therapeutic target. p53, the \nguardian of the genome, is the most important tumor suppressor. In this review, \nwe address the intertwined relationship of these two key molecules by fighting \neach other as eternal rivals in many signaling pathways. p53 represses the \npromoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its \nfamily members p63 and p73 in cancer cells lacking functional p53. Plk1 \ninhibitors target all rapidly dividing cells irrespective of tumor cells or \nnon-transformed normal but proliferating cells. Upon treatment with Plk1 \ninhibitors, p53 in tumor cells is activated and induces strong apoptosis, \nwhereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, \ninactive p53 is not associated with a susceptible cytotoxicity of Polo-like \nkinase 1 inhibition and could rather foster the induction of \npolyploidy/aneuploidy in surviving cells. In addition, compared to the \nmono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic \nor DNA damaging agents boosts more severe mitotic defects, effectually triggers \napoptosis and strongly inhibits proliferation of cancer cells with functional \np53. In this regard, restoration of p53 in tumor cells with loss or mutation of \np53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and \nprovide a proficient strategy for combating relapse and metastasis of cancer.",
"p53, sometimes referred to as the \"guardian of the genome,\" helps regulate \ncell-cycle arrest, DNA-damage repair, apoptosis, and senescence. Adding to this \nlist, in this issue of Cell Stem Cell, Liu et al. (2009) show that p53 also \nplays a role in regulating hematopoietic stem cell quiescence.",
"PURPOSE: An extensive body of literature regarding p53 has accumulated during \nthe last 2 decades. The cellular mechanisms of p53 are complex yet well-defined, \nwhereas its clinical usefulness in the management of bladder cancer remains \ncontroversial. We outline the basic constitutive functions of p53 and summarize \nits current role in the management of transitional cell carcinoma of the \nbladder.\nMATERIALS AND METHODS: We conducted a MEDLINE based literature review concerning \nthe fundamental mechanisms of p53 and its role in the management of bladder \ncancer.\nRESULTS: The p53 gene is a tumor suppressor gene that acts as \"guardian of the \ngenome.\" Many diverse cellular events, including DNA damage and hypoxia, \nactivate the p53 gene. The p53 protein functions as a transcription factor, \nregulating downstream genes involved in cell cycle arrest, DNA repair and \nprogrammed cell death. Loss of p53 function confers genomic instability, \nimpaired apoptosis and diminished cell cycle restraint. Therefore, p53 mutations \nselect for certain critical features of malignancy. Alteration of P53 is the \nmost common mutation in human cancer. Roughly half of all human malignancies, \nincluding many urological cancers, exhibit p53 mutations. In bladder cancer p53 \nmutations have been associated with higher tumor grade and advanced stage, as \nwell as progression of superficial disease to muscle invasion. Moreover, p53 \nnuclear over expression appears to be an independent predictor of disease \nprogression and decreased survival after cystectomy.\nCONCLUSIONS: The importance of p53 mutation in tumor cell biology is \nirrefutable. Wild-type p53 mediates imperative functions such as regulation of \nthe cell cycle and programmed cell death. Deficiency of p53 function by mutation \nor inactivation abrogates normal cell cycle checkpoints and apoptosis, \ngenerating a favorable milieu for genomic instability and carcinogenesis. \nHowever, despite the manifest importance of p53 in human malignancy, its current \nrole in the management of bladder cancer appears somewhat limited. A multitude \nof retrospective studies have associated p53 mutations with adverse outcomes in \nsuperficial and muscle invasive disease. Nonetheless, randomized prospective \nstudies are needed to determine the potential clinical implications of p53 in \nbladder cancer.",
"Although p53 is clearly involved in the salvage pathway to DNA damage, its \nfrequent mutations do not explain the efficacy of radiotherapy and chemotherapy. \nIndeed, around 50% of all human cancers show mutations in p53, and a further \nfraction show a functional inactivation of the protein. Nevertheless, patients \nseem to respond to therapy that would otherwise require a functional p53. At \nleast in part, these responses could be explained by the pathway mediated by \np73. This mechanism is parallel to, but independent of the p53 pathway. Several \npieces of evidence show a significant interaction between these two proteins. \nTherefore, while p53 can be rightly defined as the guardian of the genome, we \ncould think of p73 as the \"assistant\" guardian of the genome!",
"p53 is well known as the \"guardian of the genome\" for differentiated and \nneoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage \nand thus contributes to the maintenance of genomic stability. In addition to \nthis tumor suppressor function for pro-oncogenic cells, p53 also plays an \nimportant role as the central regulator of stress response by maintaining \ncellular homeostasis at the molecular and biochemical level. p53 regulates \naerobic respiration at the glycolytic and oxidative phosphorylation (OXPHOS) \nsteps via transcriptional regulation of its downstream genes TP53-induced \nglycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2). p53 \nnegatively regulates glycolysis through activation of TIGAR (an inhibitor of the \nfructose-2,6-bisphosphate). On the contrary p53 positively regulates OXPHOS \nthrough upregulation of SCO2, a member of the COX-2 assembly involved in the \nelectron-transport chain. It is interesting to notice that p53 antagonistically \nregulates the inter-dependent glycolytic and OXPHOS cycles. It is important to \nunderstand whether the p53-mediated transcriptional regulation of TIGAR and SCO2 \nis temporally segregated in cancer cells and what is the relation between these \nparadoxical regulations of glycolytic pathway with the tumor suppressor activity \nof p53. In this review we will elucidate the importance of p53-mediated \nregulation of glycolysis and OXPHOS and its relation with the tumor suppressor \nfunction of p53. Further since cellular metabolism shares great relation with \nthe process of aging we will also try and establish the role of p53 in \nregulation of aging via its transcriptional control of cellular metabolism.",
"The tumor suppressor p53 homologues, TA-p73, and p63 have been shown to function \nas tumor suppressors. However, how they function as tumor suppressors remains \nelusive. Here, I propose a number of tumor suppressor pathways that illustrate \nhow the TA-p73 and p63 could function as negative regulators of invasion, \nmetastasis, and cancer stem cells (CSCs) proliferation. Furthermore, I provide \nmolecular insights into how TA-p73 and p63 could function as tumor suppressors. \nRemarkably, the guardians--p53, p73, and p63--of the genome are in control of \nmost of the known tumor suppressor miRNAs, tumor suppressor genes, and \nmetastasis suppressors by suppressing c-myc through \nmiR-145/let-7/miR-34/TRIM32/PTEN/FBXW7. In particular, p53 and TA-p73/p63 appear \nto upregulate the expression of (1) tumor suppressor miRNAs, such as let-7, \nmiR-34, miR-15/16a, miR-145, miR-29, miR-26, miR-30, and miR-146a; (2) tumor \nsuppressor genes, such as PTEN, RBs, CDKN1a/b/c, and CDKN2a/b/c/d; (3) \nmetastasis suppressors, such as Raf kinase inhibitory protein, CycG2, and DEC2, \nand thereby they enlarge their tumor suppressor network to inhibit \ntumorigenesis, invasion, angiogenesis, migration, metastasis, and CSCs \nproliferation.",
"The tumor suppressor protein p53 is often referred to as the guardian of the \ngenome. In the past, controversial findings have been presented for the role of \nthe C-terminal regulatory domain (RD) of p53 as both a negative regulator and a \npositive regulator of p53 activity. However, the underlying mechanism remained \nenigmatic. To understand the function of the RD and of a dominant \nphosphorylation site within the RD, we analyzed p53 variants in vivo and in \nvitro. Our experiments revealed, surprisingly, that the p53 RD of one subunit \ninteracts with the DNA binding domain of an adjacent subunit in the tetramer. \nThis leads to the formation of intersubunit contacts that stabilize the \ntetrameric state of p53 and enhance its transcriptional activity in a \ncooperative manner. These effects are further modulated by phosphorylation of a \nconserved serine within the RD.",
"Tumor suppressor p53, known as 'the guardian of the genome', has the ability to \nprevent the emergence of transformed cells by the induction of cell cycle arrest \nand apoptosis. Otherwise, there were researches about the function of p53, such \nas NDA repair, regulating metabolism and maternal reproduction in recent years. \nFurthermore, there was a new function for p53 in antiviral apoptosis mentioned \nin the research, Integration of interferon-alpha/beta signaling to p53 responses \nin tumour suppression and antiviral defense. In order to define the antiviral \nfunction of p53, many target genes has been defined, such as IRF9, IRF5, ISG15 \nand TLR3. All of these implied there must be a complex mechanism for role of p53 \nin antiviral innate immunity, adaptive immunity and inflammation.",
"The tumor suppressor p53 is a multifunctional protein whose main duty is to \npreserve the integrity of the genome. This function of wild-type p53 as \n\"guardian of the genome\" is achieved at different levels, as a cell cycle \ncheckpoint protein, halting the cell cycle upon DNA damage, and via a direct \ninvolvement in processes of DNA repair. Alternatively, p53 can induce apoptosis. \nMutations in the p53 gene occur in about 50% of all human tumors and eliminate \nthe tumor suppressor functions of p53. However, many mutant p53 proteins have \nnot simply lost tumor suppressor functions but have gained oncogenic properties \nwhich contribute to the progression of tumor cells to a more malignant \nphenotype. The molecular basis for this gain of function of mutant p53 is still \nunknown. However, mutant (mut) p53 specifically binds to nuclear matrix \nattachment region (MAR) DNA elements. MAR elements constitute important higher \norder regulatory elements of chromatin structure and function. By binding to \nthese elements, mut p53 could modulate important cellular processes, like gene \nexpression, replication, and recombination, resulting in phenotypic alterations \nof the tumor cells. Mut p53 thus could be the first representative of a new \nclass of oncogenes, which exert their functions via long-range alterations or \nperturbation of chromatin structure and function.",
"With their capability to undergo unlimited self-renewal and to differentiate \ninto all cell types in the body, induced pluripotent stem cells (iPSCs), \nreprogrammed from somatic cells of human patients with defined factors, hold \npromise for regenerative medicine because they can provide a renewable source of \nautologous cells for cell therapy without the concern for immune rejection. In \naddition, iPSCs provide a unique opportunity to model human diseases with \ncomplex genetic traits, and a panel of human diseases have been successfully \nmodeled in vitro by patient-specific iPSCs. Despite these progresses, recent \nstudies have raised the concern for genetic and epigenetic abnormalities of \niPSCs that could contribute to the immunogenicity of some cells differentiated \nfrom iPSCs. The oncogenic potential of iPSCs is further underscored by the \nfindings that the critical tumor suppressor p53, known as the guardian of the \ngenome, suppresses induced pluripotency. Therefore, the clinic application of \niPSCs will require the optimization of the reprogramming technology to minimize \nthe genetic and epigenetic abnormalities associated with induced pluripotency.",
"Selenium (Se) is an essential redox-active trace element with close connections \nto cancer. Most of Se's biological functions have been attributed to the \nantioxidant properties of Se-containing proteins. However, the relative \ncontribution of selenoproteins and small Se compounds in cancer protection is \nstill a matter of debate. The tumor suppressor p53 is the most frequently \nmutated gene in human cancer and is often referred to as the \"guardian of the \ngenome\". In response to genomic stresses, p53 causes cell cycle arrest to allow \ntime for genomic damage to be repaired before cell division or induces apoptosis \nto eliminate irreparably damaged cells. Selenoprotein W (SEPW1) is a highly \nconserved small thioredoxin-like protein required for cell cycle progression. \nThe present work shows that SEPW1 facilitates the G1 to S-phase transition by \ndown-regulating expression of the cyclin-dependent kinase inhibitor p21. SEPW1 \ncontrols p21 by modulating levels of the p53 transcription factor, and this is \nassociated with changes in phosphorylation of Ser-33 in p53. More work is needed \nto identify the mechanism by which SEPW1 regulates phosphorylation of Ser-33 and \nthe kinase or phosphatase enzymes involved.",
"The tumor-suppressor gene p53 acts as \"the guardian of the genome\", sensing DNA \ndamage and initiating protective responses. To examine the hypothesis that p53 \nabnormality leads to increased genomic alterations in primary tumor cells, our \nstudy utilized 51 primary tumors of cervical carcinoma and 10 microsatellite \nmarkers. These markers were mapped to the short arms of chromosomes 3 and 5, \ncovering the regions 3p13-25 and 5p15.1-15.3. Genomic deletion on 3p and 5p was \ncorrelated with genetic or epigenetic p53 inactivation pathways, including p53 \nmutation, genetic deletion of p53 and cervical infection with human \npapillomavirus. The proportion of abnormal p53 was found to be significantly \nhigher in the cases exhibiting loss of heterozygosity (LOH) on 5p (p < 0.001), \nsupporting the hypothesis of the presence of a p53-dependent pathway to cervical \ntumorigenesis. In contrast, however, LOH on 3p was found to be independent of \np53 inactivation. A common deletion region, 3p22-24, was identified in 44% of \ninformative cases, and genomic loss at this specific region was correlated with \nearly tumorigenic onset and poor grade of tumor differentiation. Diversity \nwithin the patterns of genomic alteration in the same form of cancer suggests \ndifferent sets of risk/tumorigenic profiles, molecular pathogenesis, as well as \nprognosis and outcome.",
"The major tumour suppressor protein, p53, is one of the most well-studied \nproteins in cell biology. Often referred to as the Guardian of the Genome, the \nlist of known functions of p53 include regulatory roles in cell cycle arrest, \napoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has \nbeen implicated as a key molecular player regulating substrate metabolism and \nexercise-induced mitochondrial biogenesis in skeletal muscle. In this context, \nthe study of p53 therefore has obvious implications for both human health and \nperformance, given that impaired mitochondrial content and function is \nassociated with the pathology of many metabolic disorders such as ageing, type 2 \ndiabetes, obesity and cancer, as well as reduced exercise performance. Studies \non p53 knockout (KO) mice collectively demonstrate that ablation of p53 content \nreduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, \nreduces cytochrome c oxidase (COX) activity and peroxisome \nproliferator-activated receptor gamma co-activator 1-α protein content whilst \nalso reducing mitochondrial respiration and increasing reactive oxygen species \nproduction during state 3 respiration in IMF mitochondria. Additionally, p53 KO \nmice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) \nduring fatiguing swimming, treadmill running and electrical stimulation \nprotocols. p53 may regulate contractile-induced increases in mitochondrial \ncontent via modulating mitochondrial transcription factor A (Tfam) content \nand/or activity, given that p53 KO mice display reduced skeletal muscle \nmitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon \nmuscle contraction, p53 is phosphorylated on serine 15 and subsequently \ntranslocates to the mitochondria where it forms a complex with Tfam to modulate \nexpression of mitochondrial-encoded subunits of the COX complex. In human \nskeletal muscle, the exercise-induced phosphorylation of p53(Ser15) is enhanced \nin conditions of reduced carbohydrate availability in association with enhanced \nupstream signalling through 5'adenosine monophosphate-activated protein kinase \nbut not p38 mitogen-activated protein kinase. In this way, undertaking regular \nexercise in carbohydrate restricted states may therefore be a practical approach \nto achieve the physiological benefits of consistent p53 signalling. Although our \nknowledge of p53 in exercise metabolism has advanced considerably, much of our \ncurrent understanding of p53 regulation and associated targets is derived from \nvarious non-muscle cells and tissues. As such, many fundamental questions remain \nunanswered in contracting skeletal muscle. Detailed studies concerning the \ntime-course of p53 activation (including additional post-translational \nmodifications and subsequent subcellular translocation), as well as the effects \nof exercise modality (endurance versus resistance), intensity, duration, fibre \ntype, age, training status and nutrient availability, must now be performed so \nthat we can optimise exercise prescription guidelines to strategically target \np53 signalling. The emerging role of p53 in skeletal muscle metabolism therefore \nrepresents a novel and exciting research area for exercise and muscle \nphysiologists.",
"The tumor suppressor p53, encoded by the TP53 gene, is recognized as the \nguardian of the human genome because it regulates many downstream genes to \nexercise its function in cell cycle and cell death. Recent studies have revealed \nthat several microRNAs (miRNAs) are important components of the p53 tumor \nsuppressor network with miR-125b and miR-504 directly targeting TP53. In this \nstudy, we use a screening method to identify that two miRNAs (miR-25 and \nmiR-30d) directly target the 3'UTR of TP53 to downregulate p53 protein levels \nand reduce the expression of genes that are transcriptionally activated by p53. \nCorrespondingly, both miR-25 and miR-30d adversely affect apoptotic cell death, \ncell cycle arrest and cellular senescence. Inhibition of either miR-25 or \nmiR-30d expression increases endogenous p53 expression and elevates cellular \napoptosis in several cell lines, including one from multiple myeloma that has \nlittle TP53 mutations. Thus, beyond miR-125b and miR-504, the human TP53 gene is \nnegatively regulated by two more miRNAs: miR-25 and miR-30d.",
"The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor \nsuppressor is a phosphatase that antagonizes the phosphoinositol-3-kinase/AKT \nsignaling pathway and suppresses cell survival as well as cell proliferation. \nPTEN is the second most frequently mutated gene in human cancer after p53. \nGermline mutations of PTEN have been found in cancer susceptibility syndromes, \nsuch as Cowden syndrome, in which over 80% of patients have mutations of PTEN. \nHomozygous deletion of Pten causes embryonic lethality, suggesting that PTEN is \nessential for embryonic development. Mice heterozygous for Pten develop \nspontaneous tumors in a variety of organs comparable with the spectrum of its \nmutations in human cancer. The mechanisms of PTEN functions in tumor suppression \nare currently under intense investigation. Recent studies demonstrate that PTEN \nplays an essential role in the maintenance of chromosomal stability and that \nloss of PTEN leads to massive alterations of chromosomes. The tumor suppressor \np53 is known as a guardian of the genome that mediates the cellular response to \nenvironmental stress, leading to cell cycle arrest or cell death. Through \ncompletely different mechanisms, PTEN also protects the genome from instability. \nThus, we propose that PTEN is a new guardian of the genome. In this review, we \nwill discuss new discoveries on the role of PTEN in tumor suppression and \nexplore mechanisms by which PTEN maintains genomic stability."
] | ['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0051726', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016147', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D025521'] |
6028fc001cb411341a000102 | [
30550780
] | train | Which two antibodies directed towards the CGRP ligand, were approved by the FDA in September 2018. | list | Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. | ['Fremanezumab', 'Galcanezumab'] | [
"Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its \nreceptor (CLR + RAMP1) offer considerable improvements over existing drugs in \nmigraine prophylaxis and are the first designed to act on the trigeminal pain \nsystem. Erenumab is approved by the FDA and EMA and has reached the market since \nMay 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the \nCGRP ligand, were approved by the FDA in September 2018. To view this Bench to \nBedside, open or download the PDF."
] | nan |
51487ef9d24251bc05000031 | [
10651109,
8784230,
15853578,
15372589,
19198095,
10733264,
19589043,
21164341,
12952501,
11147511,
11147512,
14741081,
1933685,
12588639
] | train | Which two catechol-O-methyl transferase (COMT) inhibitors can be used for treatment of Parkinson disease? | list | Tolcapone (central and peripheral) and entacapone (peripheral) are catechol-O-methyl transferase inhibitors that are used for treatment of Parkinson disease. | ['tolcapone', 'entacapone'] | [
"In order to study whether the membrane hyperpolarization and firing inhibition \ncaused by dopamine and levodopa on rat midbrain dopamine cells are affected by \nthe inhibition of brain catechol-O-methyl-transferase (COMT), intracellular \nelectrophysiological recordings were made from these neurons maintained in \nvitro. Here we report that a treatment of the cerebral tissue with tolcapone, a \ncentral and peripheral inhibitor of COMT, does not change the membrane responses \nof midbrain dopamine neurons to dopamine and levodopa. The lack of modification \nof the dopaminergic effects by tolcapone suggests that the pharmacological \ninhibition of intracerebral COMT does not have detectable action on dopamine \nneurotransmission. Therefore, the therapeutic action of tolcapone in Parkinson's \ndisease, might be dependent on the reduction of COMT activity in the \nextracerebral tissue.",
"Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to \nassess the nigrostriatal dopamine system in vivo with positron emission \ntomography (PET). However, FDOPA/PET quantitation is complicated by the presence \nof the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with \nentacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) \ninhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal \nsituation to evaluate the contribution of the plasma 3OMFD fraction in several \nkinetic models of FDOPA uptake. We performed FDOPA/PET with and without the \nOR-611 preadministration in six Parkinson's disease (PD) patients. We measured \nthe time-course of the plasma FDOPA and 3OMFD fractions using high-pressure \nliquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and \nestimated the striatal FDOPA uptake rate constant graphically using the plasma \nFDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). \nWe also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model \nincorporating independent measurements of 3OMFD transport kinetic rate \nconstants. With the preadministration of OR-611, the pharmacological efficiency \nin plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed \nsignificant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p \n< 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 \nprolongs the circulation time of FDOPA in the plasma but does not alter rate \nconstants for striatal FDOPA uptake or decarboxylation.",
"Levodopa is the main pharmacologic treatment for Parkinson's disease. However, \nthe long-term administration of levodopa is associated with the development of \nmotor complications which can seriously compromise patient function. Increasing \nevidence indicates that such problems are related to abnormal pulsatile \nstimulation of striatal dopamine receptors and that treatments providing more \ncontinuous stimulation reduce the risk of motor complications. It is possible \nthat administering levodopa with a reversible catechol-O-methyl transferase \ninhibitor at frequent intervals might reduce the risk of these complications. \nStalevo (Orion) combines levodopa, the dopa-decarboxylase inhibitor carbidopa \nand the catechol-O-methyl transferase inhibitor entacapone in a single tablet. \nThis review provides an overview of the initial clinical experience gained with \nStalevo during clinical trials, including several case studies.",
"We investigated whether administration of the catechol-O-methyl transferase \n(COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the \npharmacokinetics of apomorphine in Parkinson's disease patients experiencing \nsevere motor fluctuations. In addition, the pharmacodynamics and safety of \nentacapone and apomorphine coadministration in these patients were examined. The \nstudy followed a three-sequence, three-period, crossover design. Patients were \nrandomly assigned to one of three sequences that included single oral doses of \nentacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 \nseparate test days, study treatment was administered before apomorphine. The \nstudy evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation \n[Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. \nFurthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were \nevaluated at baseline and study end. Pharmacokinetic parameters for apomorphine \n(C(max), AUC, t(max), t(1/2)) were unchanged by the administration of \nentacapone, and changes in both the tapping test and AIMS score were similar \nwith all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There \nwas no significant difference in mean total UPDRS scores between baseline and \nstudy end. The administration of entacapone did not change the pharmacokinetic \nor pharmacodynamic effects of apomorphine in these patients or prolong the \nclinical effect of apomorphine. Thus, apomorphine may be safely administered to \npatients receiving therapy with levodopa and entacapone, providing a useful \naddition to treatment for patients with advanced Parkinson's disease.",
"The year of 2007 was a turning point of the treatment of Parkinson's disease \n(PD) in Japan. Severe adverse effects of dopamine agonists including valvular \nheart disease induced by ergots and sudden onset of sleep attacks induced by \nnon-ergots, were disclosed, and treatments with agonists were reassessed. Good \nnews were marketing of ropinirole, a new non-ergot agonist, in December 2006 and \nentacapone, the first catechol-O-methyl transferase (COMT) inhibitor in Japan in \nApril 2007. Having faced these new situations, Japanese Neurological Association \nhas started revising \"the Guideline 2002 for the treatment of Parkinson's \ndisease\". Clinical trials of translational gene therapy for Parkinson's disease \nwith adeno-associated virus (AAV) vector are now going on in four approaches: \nrestoring dopamine synthetic capacity, protecting against cell death with \ntrophic factors, interfering with the aberrant protein aggregation, and \nconverting the subthalamic nucleus into an inhibitory, rather than an \nexcitatory, structure. In Japan, gene delivery of the dopamine synthesizing \nenzyme aromatic amino acid decarboxylase (AADC) to the striatum of PD patients \nis going on in Jichi Medical University. New findings of the causative genes, \nenvironmental factors and molecular mechanism of PD have provided with new tools \nfor developing new treatments. The big success of induction of induced \npluripotent stem (iPS) cells from fibroblast has given an impact on cell therapy \nresearch of PD.",
"In recent years, the treatment of Parkinson's disease has undergone an immense \namount of research, resulting in the development of multiple new medications. \nThis has largely been fuelled by dissatisfaction over the development of motor \ncomplications secondary to long term levodopa therapy. Different treatment \napproaches are applied depending on the stage of Parkinson's disease. In early \nand mild Parkinson's disease, selegiline offers a limited symptomatic effect. \nIts neuroprotective effect, although at present theoretical, has questionable \nclinical relevance. Increased mortality associated with selegiline has been \nreported, although a meta-analysis of 5 different trials did not support this \nfinding. The newer, non-ergoline dopamine agonists, pramipexole and ropinirole, \nhave undergone extensive studies to evaluate their efficacy as monotherapy in \nearly Parkinson's disease. These newer agonists are ideal initial symptomatic \nmedications, primarily because they delay the onset of levodopa-induced motor \nfluctuations. Efficacy of the newer dopamine agonists in advanced disease seems \nto be comparable to that of the older agents, bromocriptine and pergolide. \nAdverse effects can be reduced by starting the medication at a very low dose and \nthen slowly titrating upward. Catechol-O-methyl transferase (COMT) inhibitors \nare indicated for the treatment of motor fluctuations in advanced disease, \nparticularly the 'wearing-off' phenomenon. Tolcapone, a peripheral and central \nCOMT inhibitor, appears to be quite effective, producing a 47% reduction in \n'off' time. Unfortunately, 3 deaths have been observed, which are presumably \nsecondary to tolcapone therapy. The drug has been withdrawn in many countries, \nand liver enzyme testing is mandatory in the US. Entacapone, a purely peripheral \nCOMT inhibitor with a lower potency than tolcapone, has also proved to be \neffective and has not been associated with liver damage, obviating the need for \ntesting.",
"Levodopa is the most efficacious agent for the treatment of motor features of \nParkinson's disease but its chronic use is associated with the development of \nmotor complications. Mounting evidence indicates the short half-life of levodopa \nand resultant pulsatile stimulation of striatal dopamine receptors leads to \nwearing off, motor fluctuations and dyskinesias. Longer acting dopaminergic \nagents, such as dopamine agonists, are less likely to cause motor fluctuations \nand dyskinesias but are not as efficacious for control of motor symptoms. \nTherefore, there is interest in exploring ways to deliver levodopa in a more \ncontinuous fashion, in an effort to maintain benefit through the day and reduce \nthe development of motor fluctuations and dyskinesias. A dopa decarboxylase \ninhibitor (DDCI), such as carbidopa or benserazide, is administered with \nlevodopa to attenuate its peripheral conversion to dopamine, reduce nausea and \nincrease central bioavailability. When levodopa is administered with a DDCI, its \nmain route of peripheral metabolism is via catechol-O-methyl transferase (COMT). \nA COMT inhibitor can be added to the combination of levodopa and a DDCI to \nfurther extend the levodopa peripheral half-life and increase central \nbioavailability. Stalevo is a combination tablet comprised of levodopa, \ncarbidopa, and the COMT inhibitor entacapone. It is available in fixed-dose \ncombinations of levodopa/carbidopa/entacapone, 50/12.5/200, 75/18.75/200, \n100/25/200, 125/31.25/200, 150/37.5/200 and 200/50/200 mg. Stalevo is currently \napproved for use in Parkinson's disease patients with end-of-dose wearing off.",
"OBJECTIVES: Entacapone is a highly potent, reversible, peripherally acting \ncatechol-O-methyl transferase (COMT) inhibitor that is used as an adjunct to \nL-dopa in the treatment of patients with Parkinson disease (PD). Nevertheless, \nthe consequence of the long-lasting inhibition of COMT by entacapone has never \nbeen investigated. We assessed the variation of the soluble red blood cell \n(S-RBC)-COMT activity after 3 months of chronic treatment by entacapone.\nMETHODS: Twelve consecutive white PD patients (3 women and 9 men; mean age, 65.7 \n± 2.4 years) with L-dopa-related motor fluctuations were assessed. Entacapone \n200 mg was given in combination with each scheduled L-dopa/dopa decarboxylase \ninhibitor dose (range, 3-5 doses daily). The S-RBC-COMT activity was determined \nboth before entacapone administration (baseline) and twice, respectively, after \n1 and 3 months treatment with entacapone, that is, on morning, after at least a \n12-hour withdrawal of entacapone and L-dopa and before the following first daily \nadministration.\nRESULTS: Mean baseline S-RBC-COMT activity was 0.72 ± 0.09 pmol/min per \nmilligram (range, 0.30-1.29 pmol/min per milligram) of protein. After 3 months, \nthe level increased significantly in all PD patients from 0.72 ± 0.09 pmol/min \nper milligram (range, 0.30-1.29 pmol/min per milligram) to 1.19 ± 0.13 pmol/min \nper milligram (range, 0.58-2.14 pmol/min per milligram) of protein (P < 0.01), \nwhich corresponds to a mean increase of 72.9 ± 9.2% (range, 24%-146%).\nCONCLUSIONS: Our findings suggest that a long-lasting inhibition of the COMT may \nlimit the efficacy of entacapone by development of a tolerance. Moreover, one \nmay assume that an abrupt withdrawal of the treatment will be followed by a \ndramatic worsening of motor disability.",
"Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary \ncatechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down \ndegradation of levodopa and improve the availability and efficacy of each \nlevodopa dose, hence its use as a complement to levodopa/carbidopa in patients \nwith Parkinson's disease. In order to simplify the daily dosing of these \nmedications, Orion has developed an entacapone/levodopa/carbidopa combination \ntablet. Three tablet strengths are being developed so as to cover the most \ncommon clinical dosing needs. In September 2000, Orion signed a marketing and \ndistribution agreement with Novartis for the combination tablet. Under the terms \nof the agreement, Orion has exclusive marketing rights for the product in \nGermany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern \nEuropean countries. Novartis has exclusive rights to the US and territories \nother than those markets for which Orion holds market exclusivity. Orion also \nhas the option to co-promote the product in France, Spain and several other \ncountries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa \ncombination tablet (Stalevo) for the treatment of patients with idiopathic \nParkinson's disease who experience signs and symptoms of end-of-dose 'wearing \noff'. Market launch of the product is expected toward the end of 2003 in the US. \nAlso in June 2003, the Committee for Proprietary Medicinal Products of the \nEuropean Agency for the Evaluation of Medicinal Products adopted a positive \nopinion of the combination tablet. In September 2002, Orion submitted an \napplication for the approval of the combination product in the European Union. \nIt is expected that the product will be marketed in the European Union in early \n2004. Orion estimates that about two of three fluctuating Parkinson's disease \npatients will be able to be treated effectively with the triple combination \ntablet.",
"Two inhibitors of catechol-O-methyl transferase (COMT), tolcapone and \nentacapone, have recently been introduced as adjuncts to levodopa in the \ntreatment of Parkinson's disease patients. Both have been shown to provide PD \npatients with increased \"on\" time, decreased \"off\" time, and improved motor \nscores. There are, however, a number of practical issues that must be considered \nin order to achieve maximal benefits with this class of agent. They include \ndosing and administration, efficacy, adverse events, and patient education. In \ngeneral, these agents are easy to administer and well tolerated. Both the \nbenefits and the principal side effects of treatment are related to increased \ndopaminergic activity. Patients must be advised of possible side effects so that \nthey can be reported in a timely manner. Physicians must appreciate that \ndopaminergic side effects, such as dyskinesia, should be controlled by adjusting \nthe dose of levodopa and not the COMT inhibitor. Explosive diarrhea has been \nreported with tolcapone and usually necessitates discontinuing the drug. \nTolcapone must also be monitored for possible liver dysfunction. This has not \nbeen reported with entacapone, and no monitoring is required. Metabolites of \ntolcapone and entacapone may cause discoloration of the urine. This is harmless \nbut patients should be advised that this may occur.",
"Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism \nof levodopa, increase its plasma half-life, and enhance its brain availability. \nTwo COMT inhibitors, tolcapone and entacapone, have recently been made available \nas adjunctive agents to levodopa. In PD patients with motor fluctuations, they \nhave been shown to increase \"on\" time and reduce \"off\" time. In patients with \nmore advanced disease, they provide similar benefits, but patients tend to \nexperience less overall benefit and a greater likelihood of developing \ndopaminergic adverse events. Accordingly, closer monitoring is required. In \nstable patients who have not yet developed motor complications, there are \npreliminary data suggesting that they experience improvements in motor function \nand in activities of daily living. Finally, there are theoretical reasons to \nconsider administering a COMT inhibitor to patients from the onset of levodopa \ntherapy in order to reduce the likelihood that motor complications will develop. \nCOMT inhibitors are easy to administer, do not require titration, and are \ngenerally well tolerated particularly in patients with relatively mild disease. \nAdverse events are primarily dopaminergic and can usually be controlled by \nlevodopa dose adjustments. COMT inhibitors have thus proven to be a useful \naddition to the therapeutic armamentarium of PD.",
"The catechol-O-methyl transferase inhibitor entacapone is given in combination \nwith levodopa/dopa decarboxylase inhibitor for Parkinson's disease (PD) patients \nexperiencing end-of-dose wearing-off. This 4-week post-marketing surveillance \nstudy was undertaken to assess patients' responses to levodopa combined with \nentacapone in a real clinical practice setting. Overall, 466 patients with \nidiopathic PD treated with levodopa and experiencing symptoms of wearing-off \nwere recruited. Both physicians and patients recorded the response to therapy, \nincluding improvements and side-effects. Following initiation of entacapone \ntreatment, the average daily levodopa dose was reduced from 510 to 453 mg. \nPhysician assessment of entacapone efficacy was judged to be \"very good\" or \n\"good\" in 77.6% of the patients, and tolerability was considered to be \"very \ngood\" or \"good\" in 92.4% of patients, with only 12 patients (2.6%) withdrawing \nfrom the study. Compared with baseline, there was a decrease in the mean \nduration of daily 'off' time from 3.0 to 1.3 h per day during the treatment \nperiod. Adverse events were in line with those previously reported, with \ndiarrhoea being the most frequent event. The percentage of patients suffering \nfrom dyskinesia decreased from 46 to 34%, and of those patients still suffering \nfrom dyskinesia, the average daily duration of dyskinesia was reduced from 2.2 \nto 1.7 h. The use of adjunct dopamine agonists decreased from 67 to 59%. At \nstudy end, the percentage of patients who rated their quality of life (QoL) as \n\"very good\" or \"good\" increased from 12.1 to 51.7% and the percentage of \npatients who rated their QoL as \"bad\" or \"very bad\" decreased from 40 to 10.7%. \nIn summary, the results of this survey conducted in real clinical practice \nsupport the findings of previous clinical trials demonstrating the efficacy and \ntolerability of entacapone, as well as the benefits of improved QoL, for \npatients achieved with entacapone.",
"Two novel reversible enzyme inhibitors involved in monoamine metabolism are \ndescribed. The novel and reversible inhibitors are the \ncatechol-O-methyl-transferase (COMT) inhibitors, Ro 40-7592 \n(3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), and the monoamine oxidase type-B \n(MAO-B) inhibitor, Ro 19-6327 (N-(2-aminoethyl)-5-chloro-2-pyridine carboxamide \nHC1). These may be of special therapeutic benefit in Parkinson's and Alzheimer's \ndiseases.",
"We present a patient who suffered from sleep attacks after starting entacapone \nin addition to levodopa. Entacapone, a catechol-O-methyl transferase inhibitor, \nalters the pharmacokinetics of levodopa, leading to increase of levodopa \nconcentration in plasma and brain. This mechanism is suspected to be involved in \nthe pathophysiology of sleep attacks in this case."
] | ['http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D010300', 'http://www.uniprot.org/uniprot/COMT_HUMAN', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=0016206', 'http://www.uniprot.org/uniprot/COMT_RAT', 'http://www.uniprot.org/uniprot/COMT_MOUSE', 'http://www.uniprot.org/uniprot/COMT_HORSE', 'http://www.uniprot.org/uniprot/COMT_BOVIN', 'http://www.disease-ontology.org/api/metadata/DOID:14330', 'http://www.uniprot.org/uniprot/COMT_PIG'] |
5a7238d32dc08e987e000009 | [
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] | train | Which two cotransporters are inhibited by sotagliflozin? | list | Sotagliflozin works by inhibiting sodium-glucose cotransporter 1 (SGLT1) and sodium-glucose cotransporter 2 (SGLT2). It is used for treatment of diabetes. | ['sodium-glucose cotransporter 1', 'sodium-glucose cotransporter 2'] | [
"The sotagliflozin molecule exhibits two fundamentally different molecular \nconformations in form 1 {systematic name: \n(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(methylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol, \nC21H25ClO5S, (I)} and the monohydrate [C21H25ClO5S·H2O, (II)]. Both crystals \ndisplay hydrogen-bonded layers formed by intermolecular interactions which \ninvolve the three -OH groups of the xyloside fragment of the molecule. The layer \narchitectures of (I) and (II) contain a non-hydrogen-bonded molecule-molecule \ninteraction along the short crystallographic axis (a axis) whose total PIXEL \nenergy exceeds that of each hydrogen-bonded molecule-molecule pair. The \nhydrogen-bonded layer of (I) has the topology of the 4-connected sql net and \nthat formed by the water and sotagliflozin molecules of (II) has the topology of \na 3,7-connected net.",
"PURPOSE: Oral agents are needed that improve glycemic control without increasing \nhypoglycemic events in patients with type 1 diabetes (T1D). Sotagliflozin may \nmeet this need, because this compound lowers blood glucose through the \ninsulin-independent mechanisms of inhibiting kidney SGLT2 and intestinal SGLT1. \nWe examined the effect of sotagliflozin on glycemic control and rate of \nhypoglycemia measurements in T1D mice maintained on a low daily insulin dose, \nand compared these results to those from mice maintained in better glycemic \ncontrol with a higher daily insulin dose alone.\nMATERIALS AND METHODS: Nonobese diabetes-prone mice with \ncyclophosphamide-induced T1D were randomized to receive one of four daily \ntreatments: 0.2 U insulin/vehicle, 0.05 U insulin/vehicle, 0.05 U insulin/2 \nmg/kg sotagliflozin or 0.05 U insulin/30 mg/kg sotagliflozin. Insulin was \ndelivered subcutaneously by micro-osmotic pump; the day after pump implantation, \nmice received their first of 22 once-daily oral doses of sotagliflozin or \nvehicle. Glycemic control was monitored by measuring fed blood glucose and \nhemoglobin A1c levels.\nRESULTS: Blood glucose levels decreased rapidly and comparably in the 0.05 U \ninsulin/sotagliflozin-treated groups and the 0.2 U insulin/vehicle group \ncompared to the 0.05 U insulin/vehicle group, which had significantly higher \nlevels than the other three groups from day 2 through day 23. A1c levels were \nalso significantly higher in the 0.05 U insulin/vehicle group compared to the \nother three groups on day 23. Importantly, the 0.2 U insulin/vehicle group had, \nout of 100 blood glucose measurements, 13 that were <70 mg/dL compared to one of \n290 for the other three groups combined.\nCONCLUSION: Sotagliflozin significantly improved glycemic control, without \nincreasing the rate of hypoglycemia measurements, in diabetic mice maintained on \na low insulin dose. This sotagliflozin-mediated improvement in glycemic control \nwas comparable to that achieved by raising the insulin dose alone, but was not \naccompanied by the increased rate of hypoglycemia measurements observed with the \nhigher insulin dose.",
"INTRODUCTION: SGLT1 is the primary transporter responsible for the absorption of \nglucose and galactose in the intestine, while SGLT2 and SGLT1 are both involved \nin the renal reabsorption of glucose. SGLT2 inhibitors are a new class of oral \nantidiabetic drugs, acting by increasing urinary glucose excretion (UGE). They \noffer the advantages of a reduced risk of hypoglycaemia, a decrease in body \nweight and blood pressure and an efficacy at all stages of type 2 diabetes \n(T2DM).\nAREAS COVERED: Herein, the authors focus specifically on sotagliflozin (LX4211), \nthe first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English \nwere selected as the basis of this review. Clinical trials were identified using \nthe Clinicaltrial.gov database.\nEXPERT OPINION: By a potential additional mechanism of action on intestinal \nglucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from \nSGLT2 inhibitors by reducing postprandial glucose excursion and insulin \nsecretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on \nUGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 \ninhibitors on HbA1C reduction, with a similar safety profile in short-term \nstudies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 \ndevelopment as an adjuvant treatment in patients with T1DM after positive \nresults from a pilot study.",
"Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of \nantidiabetic drugs that improve glycemic control by inhibiting reabsorption of \nglucose filtered through the renal glomerulus. Use of drugs in this class has \nincreased because of their effect of decreasing body weight and a low risk for \nhypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 \ninhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual \ninhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory \neffect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent \nevidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity \nelevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin \nhormone that promotes insulin secretion in pancreatic β cells. This effect \nprobably occurs partly via inhibition of intestinal SGLT1, and the elevation of \nactive GLP-1 levels is especially apparent when these drugs are co-administered \nwith dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a \ncombination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a \nbeneficial effect associated with elevation of circulating active GLP-1 and may \nserve as a treatment for patients with type 2 diabetes.",
"OBJECTIVE: To assess the safety and efficacy of dual sodium-glucose \ncotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct \ntherapy to insulin in type 1 diabetes.\nRESEARCH DESIGN AND METHODS: We treated 33 patients with sotagliflozin, an oral \ndual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial \nassessing safety, insulin dose, glycemic control, and other metabolic parameters \nover 29 days of treatment.\nRESULTS: In the sotagliflozin-treated group, the percent reduction from baseline \nin the primary end point of bolus insulin dose was 32.1% (P = 0.007), \naccompanied by lower mean daily glucose measured by continuous glucose \nmonitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of \n0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that \nshowed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL \n(9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage \nof time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from \nbaseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = \n0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 \nmmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for \nsotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with \nsotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group.\nCONCLUSIONS: As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with \nsotagliflozin improved glycemic control and the CGM profile with bolus insulin \ndose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.",
"OBJECTIVE: Review available data on adjunctive therapies for type 1 diabetes \n(T1D), with a special focus on newer antihyperglycemic agents.\nMETHODS: Published data on hypoglycemia, obesity, mortality, and goal attainment \nin T1D were reviewed to determine unmet therapeutic needs. PubMed databases and \nabstracts from recent diabetes meetings were searched using the term \"type 1 \ndiabetes\" and the available and investigational sodium-glucose cotransporter \n(SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl \npeptidase 4 inhibitors, and metformin.\nRESULTS: The majority of patients with T1D do not meet glycated hemoglobin (A1C) \ngoals established by major diabetes organizations. Hypoglycemia risks and a \nrising incidence of obesity and metabolic syndrome featured in the T1D \npopulation limit optimal use of intensive insulin therapy. Noninsulin \nantihyperglycemic agents may enable T1D patients to achieve target A1C levels \nusing lower insulin doses, which may reduce the risk of hypoglycemia. In pilot \nstudies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist \nliraglutide reduced blood glucose, weight, and insulin dose in patients with \nT1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 \nand SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have \ndemonstrated reductions in A1C, weight, and glucose variability without an \nincreased incidence of hypoglycemia.\nCONCLUSION: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 \ninhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive \ntreatment for T1D that may help patients achieve better glucose control without \nweight gain or increased hypoglycemia.",
"Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) are the two \ndisorders which are known to share pertinent pathological and therapeutic links. \nSodium glucose co-transporter-2 (SGLT2) and Acetylcholinesterase (AChE) are \nestablished inhibition targets for T2DM and AD treatments, respectively. Reports \nsuggest that anti-diabetic drugs could be used for AD treatment also. The \npresent study used molecular docking by Autodock4.2 using our \n\"Click-By-Click\"-protocol, Ligplot1.4.3 and \"change in accessible surface area \n(ΔASA)-calculations\" to investigate the binding of two investigational \nanti-diabetic drugs, Ertugliflozin and Sotagliflozin to an established target \n(SGLT2) and a research target (human brain AChE). Sotagliflozin appeared more \npromising for SGLT2 as well as AChE-inhibition with reference to ΔG and Ki \nvalues in comparison to Ertugliflozin. The ΔG and Ki values for \n\"Sotagliflozin:AChE-binding\" were -7.16 kcal/mol and 5.6 μM, respectively while \nthe same were found to be -8.47 kcal/mol and 0.62 μM, respectively for its \ninteraction with SGLT2. Furthermore, \"Sotagliflozin:SGLT2-interaction\" was \nsubjected to (un)binding simulation analyses by \"Molecular-Motion-Algorithms.\" \nThis information is significant as the exact binding mode, interacting amino \nacid residues and simulation results for the said interaction have not been \ndescribed yet. Also no X-ray crystal is available for the same. Finally, the \nresults described herein indicate that Sotagliflozin could have an edge over \nErtugliflozin for treatment of Type 2 diabetes. Future design of drugs based on \nSotagliflozin scaffolds for treatment of Type 2 and/or Type 3 diabetes are \nhighly recommended. As these drugs are still in late phases of clinical trials, \nthe results described herein appear timely. J. Cell. Biochem. 118: 3855-3865, \n2017. © 2017 Wiley Periodicals, Inc.",
"BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is \nnot achieved with insulin therapy alone. We evaluated the safety and efficacy of \nsotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in \ncombination with insulin treatment in patients with type 1 diabetes.\nMETHODS: In this phase 3, double-blind trial, which was conducted at 133 centers \nworldwide, we randomly assigned 1402 patients with type 1 diabetes who were \nreceiving treatment with any insulin therapy (pump or injections) to receive \nsotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point \nwas a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of \nsevere hypoglycemia or diabetic ketoacidosis after randomization. Secondary end \npoints included the change from baseline in glycated hemoglobin level, weight, \nsystolic blood pressure, and mean daily bolus dose of insulin.\nRESULTS: A significantly larger proportion of patients in the sotagliflozin \ngroup than in the placebo group achieved the primary end point (200 of 699 \npatients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change \nfrom baseline was significantly greater in the sotagliflozin group than in the \nplacebo group for glycated hemoglobin (difference, -0.46 percentage points), \nweight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus \ndose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of \nsevere hypoglycemia was similar in the sotagliflozin group and the placebo group \n(3.0% [21 patients] and 2.4% [17], respectively). The rate of documented \nhypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per \nliter) or below was significantly lower in the sotagliflozin group than in the \nplacebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin \ngroup than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively).\nCONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the \nproportion of patients who achieved a glycated hemoglobin level lower than 7.0% \nwith no severe hypoglycemia or diabetic ketoacidosis was larger in the group \nthat received sotagliflozin than in the placebo group. However, the rate of \ndiabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon \nPharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .).",
"The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important \nemerging class for the treatment of diabetes. Development of SGLT2 inhibitors \nhas been oriented around a desire for high selectivity for the SGLT2 protein \nrelative to the SGLT1 protein. More recently, genetic and pharmacology research \nin mice has indicated that gastrointestinal SGLT1 inhibition may also be an \nappropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 \ninhibition in a single molecule would provide complementary insulin-independent \nmechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been \ndeveloped as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical \nfeatures of dual inhibitor of SGLT1 and SGLT2 include a large postprandial \nglucose reduction, elevation of glucagon-like peptide 1 and modest urinary \nglucose excretion. These features may have clinical implications for the use of \nsotagliflozin in the treatment of both type 1 and type 2 diabetes."
] | nan |
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] | train | Which two drugs are included in the Entresto pill? | list | Entresto includes Sacubitril and Valsartan. | ['Sacubitril', 'Valsartan'] | [
"Vasoplegia occurs in up to 16% of patients who undergo heart transplantation \n(HT) and is associated with significant morbidity and mortality. We present a \ncase of a 61-year-old man with ischemic cardiomyopathy receiving \nsacubitril/valsartan (Entresto; Novartis, Cambridge, MA) who developed profound \nhypotension after HT. He was treated with intravenous methylene blue and \nhigh-dose vasopressors, but developed acute kidney injury requiring dialysis and \na prolonged stay in the intensive care unit. This case supports a potent \nvasodilatory effect of sacubitril/valsartan, and if confirmed by other studies, \nmight warrant consideration for withholding treatment while awaiting HT, \nparticularly in patients with risk factors for vasoplegia.",
"▼ Sacubitril valsartan (Entresto-Novartis) is a new oral drug licensed for the \ntreatment of symptomatic chronic heart failure in adults with reduced ejection \nfraction.(1) It is described as an angiotensin receptor neprilysin inhibitor and \ncontains the neprilysin inhibitor, sacubitril and the angiotensin II receptor \nantagonist, valsartan.(1-3) Here, we review the evidence for sacubitril \nvalsartan and consider its place in the management of heart failure.",
"A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, \ncarvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, \nspironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice \ndaily for heart failure developed rhabdomyolysis 26 days after enalapril was \nstopped and sacubitril/valsartan (Entresto™) started. The patient received \nsacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after \n26 days she developed muscle and skin pain. Investigations revealed elevated \ncreatine kinase and liver function tests, and rhabdomyolysis with raised \ntransaminases was diagnosed. Sacubitril/valsartan and atorvastatin were \ndiscontinued and the patient was hydrated. She returned to baseline in 23 days \nand has not had any reoccurrence of rhabdomyolysis and elevated transaminases \nfor 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable \nrelationship between the patient's rhabdomyolysis and her use of \nsacubitril/valsartan. The Drug Interaction Probability Scale score was 3, \nconsistent with a possible interaction as a cause for the reaction, with \nsacubitril/valsartan as the precipitant drug and atorvastatin as the object \ndrug.",
"BACKGROUND: The effects of sacubitril/valsartan (S/V) on the \nrenin-angiotensin-aldosterone system (RAAS) in dogs with cardiomegaly secondary \nto myxomatous mitral valve disease (MMVD) are currently unknown.\nOBJECTIVES: To determine the pharmacodynamic effects of S/V on the RAAS, \nnatriuretic peptide concentrations, systolic arterial pressure (SAP), tests of \nrenal function, and serum electrolyte concentrations in dogs with cardiomegaly \nsecondary to MMVD.\nANIMALS: Thirteen client-owned dogs weighing 4-15 kg with American College of \nVeterinary Internal Medicine (ACVIM) Stage B2 MMVD.\nMETHODS: Prospective, randomized, double-blind, placebo-controlled pilot study \nof S/V in dogs with ACVIM Stage B2 MMVD.\nRESULTS: Thirteen dogs were recruited: S/V (n = 7) and placebo (n = 6). The \nmedian percentage increase in urinary aldosterone to creatinine ratio (UAldo : \nC) between day 0 and day 30 was significantly lower in the S/V group (12%; \nP = .032) as compared with the placebo group (195%). The median percentage \ndecrease of NT-proBNP concentration from day 0 to day 30 was not statistically \ndifferent between groups (P = .68). No statistical differences were seen in \nechocardiographic, thoracic radiographic, SAP, or serum biochemical test results \nmeasured at any time point between groups. No adverse events were observed for \ndogs in either group.\nCONCLUSION AND CLINICAL IMPORTANCE: Sacubitril/valsartan may provide a new \npharmaceutical method to effectively inhibit the RAAS in dogs with ACVIM Stage \nB2 MMVD.",
"A novel antihypertensive drug, LCZ696 (Entresto®), has recently been introduced, \nwhich combines the action of an antagonist of the renin-angiotensin-aldosterone \nsystem (RAAS), effectively decreasing the blood pressure, with an inhibition of \nneprilysin, which is responsible for metabolizing natriuretic peptides exerting \nantihypertensive and antifibrotic effects. In this MiniReview, we describe the \npharmacokinetics and pharmacodynamics, efficacy and side effects of the combined \nangiotensin receptor antagonist and neprilysin inhibitor LCZ696. We summarize \nthe effect of LCZ696 treatment of patients suffering from hypertension and heart \nfailure (HF) and further highlight the role of this new drug as a treatment \noption in the future. In the earlier stages of the treatment of patients with \nheart failure, LCZ696 was superior in lowering the blood pressure compared to \nolmesartan, while the effect on blood pressure at long-term treatment was \ncomparable for the two drugs. The numbers of adverse effects were comparable. \nLCZ696 was superior to enalapril in reducing mortality, hospitalizations and HF \nsymptoms. Adverse effects were reduced with a slower up-titrating regimen of 6 \nweeks. The current results are promising and suggest that LCZ696 will be a new \ncandidate for first-line treatment of HF. However, it needs to be explored \nwhether LCZ696 is safe in pregnant women, what are the effects of long-term \nLCZ696 treatment on survival and whether the antifibrotic effects can be of \nmajor benefit in, for example HF with preserved ejection fraction.",
"The last decade has witnessed extensive growth in the field of \nco-crystallization for mitigating the solubility and dissolution-related issues \nof poorly soluble drugs. This is largely because co-crystals can modify the \nphysicochemical properties of drugs without any covalent modification in the \ndrug molecules. The US Food and Drug Administration (FDA) now considers drug \nproducts that are designed to contain a new co-crystal, analogous to new \npolymorph of the active pharmaceutical ingredient (API). This positive change in \nregulatory perspective coupled with successful commercialization of \nvalsartan-sacubitril co-crystal (Entresto, Novartis) has now brought co-crystals \ninto focus, in both industries as well as academia. Co-crystal prediction, \nscreening, and synthesis have been reported in literature; however, co-crystal \nproduction at a larger scale needs further investigations. With this aim, the \narticle describes various continuous methods for co-crystal production, along \nwith in-line monitoring during co-crystal production, emphasizing on process \nanalytical technology (PAT). In addition, the scale-up issues of continuous and \nbatch co-crystallization and other suitable techniques for pharmaceutical scale \nup are detailed. Quality control aspects and regulatory viewpoint crucial for \ncommercial success are elaborated in the future perspective.",
"Author information:\n(1)School of Medicine, Oregon Health & Science University, Portland, OR, USA.\n(2)Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & \nScience University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. \nprasad@ohsu.edu.\n(3)Department of Public Health and Preventive Medicine, Oregon Health & Science \nUniversity, Portland, OR, USA. prasad@ohsu.edu.\n(4)Center for Health Care Ethics, Oregon Health & Science University, Portland, \nOR, USA. prasad@ohsu.edu.",
"Heart failure affects ≈5.7 million people in the United States alone. \nAngiotensin-converting enzyme inhibitors, angiotensin receptor blockers, \nβ-blockers, and aldosterone antagonists have improved mortality in patients with \nheart failure and reduced ejection fraction, but mortality remains high. In July \n2015, the US Food and Drug Administration approved the first of a new class of \ndrugs for the treatment of heart failure: Valsartan/sacubitril (formerly known \nas LCZ696 and currently marketed by Novartis as Entresto) combines the \nangiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug \nsacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is \nconverted by esterases to LBQ657, which inhibits neprilysin, the enzyme \nresponsible for the degradation of the natriuretic peptides and many other \nvasoactive peptides. Thus, this combined angiotensin receptor antagonist and \nneprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart \nfailure: activation of the renin-angiotensin-aldosterone system and decreased \nsensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With \nACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure \n(PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and \nhospitalization for heart failure, as well as blood pressure, compared with \nenalapril in patients with heart failure, reduced ejection fraction, and an \nelevated circulating level of brain natriuretic peptide or N-terminal pro-brain \nnatriuretic peptide. Ongoing clinical trials are evaluating the role of \nvalsartan/sacubitril in the treatment of heart failure with preserved ejection \nfraction and hypertension. We review here the mechanisms of action of \nvalsartan/sacubitril, the pharmacological properties of the drug, and its \nefficacy and safety in the treatment of heart failure and hypertension.",
"Sacubitril/valsartan (Entresto) for chronic heart failure; brexpiprazole \n(Rexulti) for major depressive disorder and schizophrenia; and \nlumacaftor/ivacaftor (Orkambi) for cystic fibrosis involving specific CFTR \nmutations.",
"In this article, we consider the new drugs approved for the European market in \n2015. We present a summary of the new mechanisms of action introduced and \nhighlight three new mechanisms of action with a potentially high future impact: \nPCSK9 inhibition (alirocumab (Praluent®) and evolocumab (Repatha®)) for \nhypercholesterolaemia, neprilysin inhibition (sacubitril in combination with \nvalsartan (Entresto®)) for heart failure, and interleukin-5 inhibition \n(mepolizumab (Nucala®)) for asthma.",
"Heart failure (HF) is one of the leading causes of morbidity, mortality, and \nhealth care expenditures in the US and worldwide. For three decades, the pillars \nof treatment of HF with reduced ejection fraction (HFrEF) were medications that \ntargeted the sympathetic nervous system (SNS) and the \nrenin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the \nnatriuretic peptide system (NPS) for the management of HF failed either due to \nlack of significant clinical benefit or due to the unacceptable side effect \nprofile. This review article will discuss the NPS, the failure of early drugs \nwhich targeted the NPS as therapies for HF, and the sequence of events which led \nto the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). \nLCZ696 has been shown to be superior to the standard of care available for \ntreatment of HFrEF in several substantial hard endpoints including heart failure \nhospitalizations, cardiovascular mortality, and all-cause mortality.",
"AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in \npatients with chronic heart failure (CHF) and can play a detrimental role in the \npathophysiology course of CHF. However, the best way to manage SDB in CHF \nremains a matter of debate. Sacubitril-valsartan has been included in the 2016 \nEuropean Society of Cardiology guidelines as an alternative to \nangiotensin-converting enzyme inhibitors to further reduce the risk of \nprogression of CHF, CHF hospitalization, and death in ambulatory patients. \nSacubitril and valsartan are good candidates for correcting SDB of CHF patients \nbecause their known mechanisms of action are likely to counteract the \npathophysiology of SDB in CHF.\nMETHODS AND RESULTS: The ENTRESTO-SAS trial is a 3-month, multicentric, \nprospective, open-label real-life cohort study. Patients eligible for \nsacubitril-valsartan treatment (i.e. adults with left ventricular ejection \nfraction ≤35%, who remain symptomatic despite optimal treatment with an \nangiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid \nreceptor antagonist) will be evaluated before and after 3 months of treatment \n(nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and \nquality-of-life and SDB questionnaires). The primary outcome is the change in \nthe Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred \ntwenty patients are required to detect a significant 20% improvement of the \nApnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%.\nCONCLUSIONS: In the context of the SERVE-HF study, physicians are waiting for \nnew trials and alternative therapies. We sought to assess in the ENTRESTO-SAS \ntrial whether sacubitril-valsartan could improve the outcome of SDB in CHF \npatients.",
"The main stay pharmacotherapy for heart failure (HF) is targeted towards \nrennin-angiotensin-aldosterone (RAAS) and neprilysin pathways (NP). Both \ntherapeutic strategies decreases morbidity and mortality but also carry \nconsiderable adverse effects. This review of the literature highlights the new \ngeneration of HF drug, sacubitril-valsartan (SV), trade name Entresto \n(researched as LCZ696, Novartis) which simultaneously blocks RAAS and NP. This \ndual action of angiotensin receptors blocker and neprilysin inhibitor (NPi) has \nimproved HF prognosis and it is an evolution in the management of HF. Although \nthe initial follow-up of patients treated with SV has yielded promising results, \nthere are concerns regarding potential side effects especially an increase in \nthe risk of Alzheimer's disease (AD) and young onset of AD. NPi interferes with \nthe breakdown and clearing of beta-amyloid peptides, the plaques seen in AD, \nraising concern for AD in SV patients. On the other hand, hypertension and \ncardiovascular diseases are established risk factors for AD which can be \ndecreased by SV therapy. It is therefore essential that SV treated patients are \nfollowed up over an extended period of time to detect any adverse cognitive \nchanges.",
"BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) makes up half \nof diagnosed heart failure (HF) cases and has similar outcomes compared to heart \nfailure with reduced ejection fraction (HFrEF) but a discrepancy in knowledge \nand approach to treatment. HFpEF is diagnosed using the following criteria: \nsymptoms, preserved ejection fraction (greater than 50%), and evidence of \nabnormal left ventricular filling or relaxation, or diastolic distensibility or \nstiffness. Studies conducted to examine the efficacy of angiotensin receptor \nblockers (ARB) (irbesartan and candesartan), thiazide diuretics \n(chlorthalidone), and angiotensin converting enzyme inhibitors (ACEI) \n(perindopril) in the treatment of HFpEF, showed moderate efficacy but no clear \nbenefit. Recently, the FDA has approved a novel drug, which combines an \nangiotensin receptor neprilysin inhibitor and ARB (valsartan) named LCZ696 \n(entresto) for possible treatment of HFrEF.\nCONCLUSION: In this article, we will discuss the failure of previous treatment \nmodalities and the promise that LCZ696 (entresto) may hold for treating patients \nwith HFpEF.",
"Heart Failure (HF) is one of the main healthcare burdens in the United States \nand in the world. Many drugs are approved and used in practice for management of \nthis condition; including beta blockers, diuretics, aldosterone antagonists, \nAngiotensin Converting Enzyme Inhibitors (ACEI's), and Angiotensin Receptor \nBlockers (ARBs). Recently, the Food and Drug Administration (FDA) approved a \ndrug with brand name Entresto (Sacubitril/Valsartan or LCZ696), an angiotensin \nreceptor neprilysin inhibitor for the use in Heart Failure with Reduced Ejection \nFraction (HFrEF) patients instead of ACEI's and ARBs. The drug works through \nangiotensin receptor blockage via valsartan as well as neprilysin inhibition \nwith sacubitril. This represented a new milestone in managing heart failure \npatients and provided yet another therapy in our armamentarium. This article \nreviews the stages that led to the development of this drug, the failure of its \npreceding agents, the lessons we have learnt, and the current trials of Entresto \nfor new indications.",
"Sacubitril/valsartan [LCZ696 (Entresto), Novartis Pharmaceuticals Corp.] is the \nfirst in a new class of drugs that combines neprilysin inhibition with \nangiotensin II receptor antagonism, the combination of which acts to increase \nendogenous natriuretic peptides while inhibiting the \nrenin-angiotensin-aldosterone system. Sacubitril/valsartan has been studied in \nthe treatment of hypertension, heart failure with reduced ejection fraction \n(HFrEF), and heart failure with preserved ejection fraction (HFpEF) and has \ndemonstrated clinical efficacy in blood pressure reduction in hypertensive \npatients with and without HFpEF and a reduction in hospitalizations and \nmortality for patients with HFrEF. Research to evaluate clinical outcomes in \nHFpEF is ongoing. Sacubitril/valsartan is approved to reduce hospitalization and \nrisk of cardiovascular death for patients with HFrEF in New York Heart \nAssociation (NYHA) functional class II-IV. The product is as well tolerated as \nan angiotensin-converting enzyme inhibitor, with the most common side effect \nbeing hypotension. Expectedly, it is much more costly than generic \nangiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, \nwhich will be a factor in determining how widespread the use of this agent will \nbe. In summary, although the number of published studies evaluating its use is \nlimited, sacubitril/valsartan represents a promising new treatment option for \npatients with HFrEF. Ongoing studies will continue to refine the role of this \nagent in clinical practice.",
"Entresto was recommanded by major guidelines as the frontline therapy for heart \nfailure with reduced ejection fraction since its clinical benefit was proved by \nthe PARADIGM-HF trial. Angiotensin converting enzyme inhibitors are the \ncornerstone of the treatment of HF. Varying incidences of first-dose hypotension \nhave been reported and recognized as a potential limiting factor for \nprescribing. According to previous reports, the onset of hypotension mostly \noccur 3-5 hours after the first dose. However, the pattern of entresto-related \nhypotension has not been reported. We present a case of HF, who had delay onset \n(about 8 to 18 hours) and prolonged (3 to 6 days) first-dose hypotension. \nFurther investigation is required to illustrate this phenomenon.",
"The molecular combination of sacubitril and valsartan (Entresto) is a new drug \nfor reducing the risk of cardiovascular death and hospitalization for heart \nfailure in patients with chronic heart failure (NYHA Class II-IV) and reduced \nejection fraction. It is usually administered in conjunction with other heart \nfailure therapies, instead of an ACE inhibitor or an angiotensin-receptor \nblocker (ARB). In studies, sacubitril/ valsartan was superior to enalapril in \nreducing the risks of death and hospitalization for heart failure. Possible side \neffects of sacubitril/valsartan are hypotension, angioedema, impaired renal \nfunction and elevation in serum potassium levels. The drug should not be used in \ntimes of pregnancy and breast feeding, in patients with servere hepatic \nimpairment (Child-Pugh C) and in combination with aliskiren in patients with \ndiabetes."
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] | train | Which two drugs are included in the Harvoni pill? | list | Harvoni contains 400 mg sofosbuvir and 90 mg ledipasvir. It used for treatment of hepatitis C virus infection. | ['sofosbuvir', 'ledipasvir'] | [
"Nucleotide compounds like sofosbuvir, acyclovir, and tenofovir have proven to be \namongst the most potent orally available antiviral treatments. These drugs \nexhibit high efficacy and a wide therapeutic index, with demonstrated utility in \na number of chronic viral infections. The approval of Sovaldi™, brand name for \nsofosbuvir, by the U.S. Food and Drug Administration heralded improvements in \nchronic hepatitis C virus (HCV) treatment. Sofosbuvir was originally discovered \nby Pharmasset Corporation and named PSI-7977. It was subsequently acquired and \nadvanced through phase 3 development by Gilead Sciences, Inc. In Sofosbuvir both \na unique pharmacology and a high specificity for the HCV ribonucleic acid \npolymerase are present in a molecule that is well tolerated and highly \nefficacious. Phase 2 and 3 clinical trials have consistently demonstrated \ndurable and high rates of sustained virologic response (SVR), curing patients in \nexcess of 80% in all genotypes and >90% in treatment-naïve subjects being \nadministered combination therapy with other agents. Harvoni(®) is the \ncombination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral \ntablet, and it has demonstrated high SVR rates in patients infected with HCV \ngenotype 1, without the need for exogenous interferon and/or ribavirin. Here, we \ndiscuss the discovery, development, pharmacologic characterization, and results \nfrom the phase 3 trials of sofosbuvir. Hepatitis C is a chronic disease, for \nwhich most patients have been undiagnosed, are unwilling to start treatment, or \nare ineligible for treatment because of the high toxicity and low efficacy of \ninterferon and ribavirin-based therapy. Clinical studies with sofosbuvir have \ndemonstrated significant improvement over the prior standard of care, thus \nushering in a new paradigm of HCV treatment and an update of treatment \nguidelines.",
"PURPOSE: Public discourse regarding the hepatitis C virus (HCV) drug Sovaldi® \n(sofosbuvir) has become inflamed, generating much heat but little light \nconcerning the clinical, health economic, and quality-of-life merits of \nSovaldi®. The purpose of this article is to provide a factual basis for \nevaluating the claims regarding the benefits of Sovaldi® relative to its costs.\nMETHODS: A comprehensive review was conducted of news stories highlighted in the \ndaily updates of the electronic newsletters BIO SmartBrief, FiercePharma, \nFierceBiotech and BioCentury Extra published from November 1, 2013, through \nDecember 31, 2014, on the topics of the HCV market, Sovaldi®, and other HCV \ntherapeutics. Also reviewed were recent practice guidelines on the management of \nHCV infections, prescribing information on all HCV drugs approved by the US Food \nand Drug Administration, and health technology assessments of Sovaldi® and \nHarvoni(TM) (sofosbuvir/ledipasvir).\nFINDINGS: Sovaldi® and Harvoni(TM) have provided significant improvements in the \ntreatment of HCV, with all-oral regimens and cure rates exceeding 90% in some \npopulations of patients with HCV. Sovaldi® prevents significant health care \nresource utilization in patients who would otherwise develop cirrhosis and \nrequire a liver transplant; however, only a small proportion of patients with \nHCV develop cirrhosis, and fewer require liver transplants. Because it is not \npossible to identify those patients whose HCV will progress to severe liver \ndisease, it would be necessary to treat a large number of patients with HCV to \nprevent disease progression in this subpopulation, resulting in a considerable \nloss to health plans even over a 20-year horizon. The claim that treating all \npatients with HCV with Sovaldi® would cost nearly as much as the current total \nUS expenditure on all prescription drugs, while factually correct, is not a \nrealistic scenario. Many patients with HCV will continue to go undiagnosed. In \naddition, the medical expense for those who are treated will be spread out over \nmany years. However, the unexpectedly large, up-front cost of covering these \ndrugs has had a major impact on health plan budgets, resulting in losses for \nsome plans.\nIMPLICATIONS: Sovaldi® represents an enormous advance in the care of some \npopulations of HCV-infected patients, but also a major cost burden to health \nplans. As the first of a number of anticipated, paradigm-changing drugs to treat \nmedical conditions affecting large patient populations, Sovaldi® should act as a \nwake-up call for all health care stakeholders to engage in a meaningful, \nfact-based discussion about managing the cost of innovative new drugs to balance \nthe needs of drug manufacturers, health plans, providers, and, above all, \npatients.",
"Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A \ninhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in \nthe US, European Union, Canada, and other regions for the treatment of chronic \nhepatitis C virus infection in adults. Following absorption, ledipasvir reaches \nmaximum plasma concentrations (T max) 4-4.5 h post-dose and is eliminated with a \nterminal half-life (t 1/2) of 47 h. Sofosbuvir undergoes intracellular \nactivation to an active triphosphate GS-461203 (not detected in plasma) and \nultimately to GS-331007, a predominant circulating metabolite, which is the \nprimary analyte of interest in clinical pharmacology studies. Sofosbuvir is \nrapidly absorbed and eliminated from plasma (T max: 0.8-1 h; t 1/2: 0.5 h). The \npeak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h \npost-dose; the elimination t 1/2 for GS-331007 is 27 h. Ledipasvir/sofosbuvir \nexhibits a favorable clinical pharmacology profile; it can be administered once \ndaily without regard to food and does not require dose modification in hepatitis \nC virus-infected patients with any degree of hepatic impairment or mild to \nmoderate renal impairment. The pharmacokinetic profiles of ledipasvir, \nsofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are \nnot significantly affected by demographic variables; \npharmacokinetic/pharmacodynamic analyses reveal no exposure-response \nrelationships for efficacy or safety. The review summarizes the clinical \npharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses \nfor ledipasvir/sofosbuvir.",
"The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor \nledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir \n(ledipasvir/sofosbuvir; Harvoni(®)) was recently approved in the US and the EU. \nThe phase III ION trials included treatment-naive (ION-1 and -3) or \ntreatment-experienced (ION-2) patients with chronic HCV genotype 1 infection \n(≈20 % of patients in ION-1 and -2 had cirrhosis, whereas no patient in ION-3 \nhad cirrhosis). A sustained virological response 12 weeks' post-treatment \n(SVR12) was seen in 99 % of treatment-naive patients receiving \nledipasvir/sofosbuvir for 12 weeks in ION-1, with no additional benefit \nconferred by the addition of ribavirin or extending the treatment duration to 24 \nweeks. Moreover, in ION-3, an 8-week regimen achieved an SVR12 rate of 94 % \noverall and 97 % in the subgroup of patients with a baseline HCV RNA level of <6 \nmillion IU/mL. SVR12 rates of 94 and 99 % were seen in treatment-experienced \npatients who received ledipasvir/sofosbuvir for 12 and 24 weeks in ION-2. Data \nalso support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 \ninfection, in HCV and HIV co-infection and, in combination with ribavirin, in \npatients with chronic HCV genotype 1 or 4 infection who have decompensated \ncirrhosis or are liver transplant recipients and in chronic HCV genotype 3 \ninfection. Oral ledipasvir/sofosbuvir was generally well tolerated. In \nconclusion, ledipasvir/sofosbuvir is an important new single-tablet regimen that \nrepresents a significant advance in the treatment of chronic hepatitis C.",
"BACKGROUND: New treatments for hepatitis C (HCV) infection hold great promise \nfor cure, but numerous challenges to diagnosing, establishing care, and \nreceiving therapy exist. There are limited data on insurance authorization for \nthese medications.\nMATERIALS AND METHODS: We performed a retrospective chart review of patients \nreceiving sofosbuvir/ledipasvir (SOF/LED) from October 11-December 31, 2014 to \ndetermine rates and timing of drug authorization. We also determined predictors \nof approval, and those factors associated with faster decision and approval \ntimes.\nRESULTS: Of 174 patients prescribed HCV therapy during this period, 129 requests \nwere made for SOF/LED, of whom 100 (77.5%) received initial approval, and an \nadditional 17 patients (13.9%) ultimately received approval through the appeals \nprocess. Faster approval times were seen in patients with Child-Pugh Class B \ndisease (14.4 vs. 24.7 days, p = 0.048). A higher proportion of patients were \ninitially approved in those with Medicare/Medicaid coverage (92.2% vs. 71.4%, p \n= 0.002) and those with baseline viral load ≥ 6 million IU/mL (84.1% vs. 62.5%, \np = 0.040). Linear regression modeling identified advanced fibrosis, high Model \nof End Stage Liver Disease (MELD) score, and female gender as significant \npredictors of shorter decision and approval times. On logistic regression, \nMedicare/Medicaid coverage (OR 5.96, 95% CI 1.66-21.48) and high viral load (OR \n4.52, 95% CI 1.08-19.08) were significant predictors for initial approval.\nCONCLUSIONS: Early analysis of real-world drug authorization outcomes between \nOctober-December 2014 reveals that nearly one in four patients are initially \ndenied access to SOF/LED upon initial prescription, although most patients are \neventually approved through appeal, which delays treatment initiation. Having \nMedicare/Medicaid and advanced liver disease resulted in a higher likelihood of \napproval as well as earlier decision and approval times. More studies are needed \nto determine factors resulting in higher likelihood of denial and to evaluate \napproval rates and times after implementation of restrictive prior authorization \nguidelines.",
"Ledipasvir/Sofosbuvir (harvoni): improving options for hepatitis C virus \ninfection.",
"Chronic hepatitis C (CHC) affects over 185 million individuals worldwide, \napproximately 3% of the world's population. CHC can lead to quality of life \nimpairment, cirrhosis, hepatocellular carcinoma (HCC), liver failure and \nliver-related death. While CHC has been associated with increases in HCC, \nliver-related mortality and all-cause mortality, being cured of CHC is \nassociated with improvement in these outcomes. Older interferon-based regimens \nwere complex and toxic and required 6-12 months of therapy, with cure rates \naveraging around 40-45% for HCV genotype 1. Newer interferon-free regimens are \nnow available in the US, Europe, Japan and in other countries. These regimens \nhave short durations, minimal side effects, low pill burden and efficacy \napproaching 90-100%. We may eventually see single-tablet regimens lasting no \nmore than 4-6 weeks. This review will summarize the data regarding these \ninterferon-free regimens, including Gilead's Harvoni (sofosbuvir/ledipasvir), \nAbbVie's Viekira Pak (paritaprevir/ritonavir/ombitasvir with dasabuvir), and \nJanssen's Olysio (simeprevir) with sofosbuvir. Some practical considerations as \nwe move into an interferon-free era will also be discussed, such as patient \nadherence and drug-drug interactions.",
"Author information:\n(1)Second Liver Cirrhosis Diagnosis and Treatment Center, 302 Hospital, Beijing, \nChina.\n(2)Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, \nPeking University People's Hospital, Peking University Hepatology Institute, \nBeijing, China.\n(3)Division of Gastroenterology & Hepatology, Humanity & Health Medical Centre, \nHong Kong, Hong Kong SAR, China.\n(4)The Translational Hepatology Institue, Beijing You'an Hospital, Capital \nUniversity of Medicine, Beijing, China.\n(5)Department of Infectious Diseases, Shengjing Hospital, China Medical \nUniversity, Shenyang, China.\n(6)Department of Infectious diseases, Shanghai Ruijin Hospital, Jiaotong \nUniversity, School of Medicine, Shanghai, China.\n(7)Key Laboratory of Medical Molecular Virology, Huashan Hospital, Fudan \nUniversity, Shanghai, China Institute of Biomedical Sciences, Shanghai Medical \nCollege, Fudan University, Shanghai, China.\n(8)Department of Gastroenterology, Shanghai First People's Hospital, Shanghai \nJiao Tong University School of Medicine, Shanghai, China.\n(9)Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University \nSchool of Medicine, Shanghai, China.\n(10)Liver Disease Center, Beijing Ditan Hospital, Capital University of \nMedicine, Beijing, China.\n(11)Department of Infectious Diseases, Center for Liver Diseases, Peking \nUniversity First Hospital, Beijing, China.\n(12)Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing \nUniversity of Medical Sciences, Chongqing, China.\n(13)Department of Infectious Disease, Xijing Hospital, Fourth Military Medical \nUniversity, Xi'an, China.\n(14)Department of Infection, Sichuan Provincial People's Hospital, Chengdu, \nSichuan, China.\n(15)Center of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, \nTangdu Hospital, Fourth Military Medical University, Xi'an, China.\n(16)Shanghai Liver Diseases Research Center, Nanjing Military Command, Shanghai, \nChina.\n(17)People's Hospital, Shanghai Jiaotong University, School of Medicine, \nShanghai, China.\n(18)Department of Infectious Diseases, Henan Provincal People's Hospital, \nZhengzhou University, Zhengzhou, China.\n(19)Department of Infectious Disease, Xinjiang Medical University First \nAffiliated Hospital, Urumqi, China.\n(20)Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical \nUniversity, Xi'an, China.\n(21)Liver Disease Center for Combined Traditional Chinese Medicine and Western \nMedicine, 302 Hospital, Beijing, China.\n(22)State Key Laboratory of Organ Failure Research, Guangdong Provincial Key \nLaboratory of Viral Hepatitis Research, Department of Infectious Diseases, \nNanfang Hospital, Southern Medical University, Guangzhou, China.\n(23)Liver Disease Center, Beijing Friendship Hospital, Capital Medical \nUniversity, Beijing, China.\n(24)Department of Microbiology and Center of Infectious Disease, School of Basic \nMedical Sciences, Peking University Health Science Center, Beijing, China.",
"Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection; \ndulaglutide (Trulicity) for glycemic control in type-2 diabetes; \nnetupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related \nto chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in \npatients with chronic noncancer pain.",
"The long awaited all-oral therapy for hepatitis C virus infection has officially \nbeen inaugurated by the registration of the hepatitis C nucleotide inhibitor \nsofosbuvir in a combination regimen with ribavirin. More recently, the oral \narray to treat hepatitis C has been enriched by the arrival of the NS5A \ninhibitors ledipasvir (also in a single formulation with sofosbuvir, Harvoni(®)) \nand daclatasvir; the protease inhibitor simeprevir, and the Viekirax(®)+Exviera™ \nregimen based on the ritonavir boosted protease inhibitor paritaprevir; the NS5A \ninhibitor ombitasvir, and the non-nucleoside inhibitor dasabuvir. Owing to the \nbudget-breaking price of the newer oral medicines, the Italian National Health \nSystem elected to restrict reimbursement of oral anti-hepatitis C therapy to \npatients with advanced liver disease or transplanted organs, and those who are \ninterferon unable, only. While this therapeutic strategy harmonizes with \nprinciples of distributive justice, at the same time it fuelled the argument of \nits doubtful cost-effectiveness, owing to the National Health System's \nreimbursement of the sole sofosbuvir+ribavirin regimen, which has suboptimal \nefficacy against the prevalent hepatitis C virus genotype 1b. As a consequence, \nwe are left with a number of uncertainties regarding the optimal treatment \nmodality for certain subgroups of hepatitis C patients, and the clinical \nbenefits provided by hepatitis C virus clearance in patients with advanced liver \ndisease.",
"The availability of direct-acting antiviral (DAA) therapy has launched a new era \nin the management of chronic hepatitis C. Sofosbuvir, a uridine nucleotide \nanalog that inhibits the hepatitis C RNA-dependent RNA polymerase, is the \nbackbone of chronic hepatitis C therapy. Acting at the catalytic site of the \npolymerase, sofosbuvir is highly potent in suppressing viral replication and has \na high genetic barrier to resistance. Sofosbuvir is effective across all \nhepatitis C genotypes, and is a mainstay of interferon-free combination therapy. \nIn Phase II and III studies, genotype 1 patients who took sofosbuvir in \ncombination with another DAA such as the NS3-4A protease inhibitor, simeprevir, \nor the NS5A replication complex inhibitors, ledipasvir or daclatasvir, achieved \na sustained virologic response rate of over 90%. Harvoni(®), a combination \ntablet of sofosbuvir and ledipasvir, dosed once daily is recommended for 24 \nweeks for treatment-experienced genotype 1 patients with cirrhosis, but 12 weeks \nof therapy is sufficient for all other populations. While genotype 2 (12 weeks \nor 16 weeks) and treatment-naïve genotype 3 patients (24 weeks) have excellent \nresponse rates with sofosbuvir and ribavirin, treatment-experienced cirrhotic \ngenotype 3 patients may need the addition of another DAA such as daclatasvir. \nSofosbuvir is efficacious in special populations such as HIV-hepatitis C \nvirus-coinfected patients and liver transplant recipients and has already made a \nprofound impact in these groups. Since it is renally eliminated, patients with \nadvanced kidney disease or on dialysis must await dosing recommendations. \nSofosbuvir-based regimens appear to be well tolerated with headache and fatigue \nbeing the most common side effects. The opportunity to cure patients with \nhepatitis C with sofosbuvir combination therapy is likely to change the future \nfor our patients, particularly if the emphasis shifts to identifying those \npatients unaware that they are infected and providing affordable access to \ntreatment.",
"Treatment for chronic hepatitis C depends on the hepatitis C virus (HCV) \ngenotype and the patient's clinical characteristics. A fixed-dose combination of \nledipasvir + sofosbuvir has been authorised in the European Union for adults \nwith HCV genotype 1 (HCV-1), HCV-3 or HCV-4 infection. Ledipasvir targets the \nHCV protein NS5A, while sofosbuvir inhibits the HCV RNA polymerase NS5B. The \nledipasvir+ sofosbuvircombination has not been compared directly with other \nantiviral drugs. No information is available on its ability to prevent hepatic \ncomplications, even in patients with cirrhosis. In four trials including over \n1800 treatment-naive patients infected with HCV-1, a 12-week course of \nledipasvir + sofosbuviryielded a sustained virological response in nearly every \ncase. This is better than that reported with peginterferon alfa-based protocols. \nIn four trials including more than 900 HCV-1-infected patients in whom \ntreatments including peginterferon alfa had failed, a 24-week course of \nledipasvir+ sofosbuvir yielded a sustained virological response in nearly every \ncase, which is far better than reported with peginterferon alfa + ribavirin + \nprotease inhibitor combinations, based on indirect comparison. In these trials, \na 24-week course of the ledipasvir + sofosbuvir combination was effective in \nalmost all patients with compensated cirrhosis. The same treatment also showed \nmajor efficacy in a non-comparative trial in 337 HCV-1-infected patients with \ndecompensated cirrhosis or who had undergone liver transplantation. In mid-2015, \nvery few data are available on the ledipasvir + sofosbuvir combination in \nHCV-1-infected patients in whom sofosbuvir combination therapy has failed, or in \npatients with HCV-3 or HCV-4 infection. Comparative data on the adverse effects \nof the ledipasvir + sofosbuvir combination are mainly based on a double-blind, \nplacebo-controlled trial in 155 patients. Overall, serious adverse effects were \ninfrequent in this and other trials. The main adverse effects appear to be \nheadache, fatigue, sleep disorders, irritability and lipase elevations. \nHypertension, muscle disorders and dyspnoea are other plausible adverse effects. \nBradycardia and cardiac conduction disorders have been reported with concomitant \nuse of sofosbuvir and amiodarone, an antiarrhythmic drug. In practice, in \nmid-2015, when drug therapy is warranted for chronic hepatitis C due to HCV \ngenotype 1, the ledipasvir + sofosbuvir combination is a first-choice treatment \nbecause of its virological efficacy, despite its poorly documented adverse \neffects. These important outstanding questions call for rigorous \npharmacovigilance on the part of all healthcare professionals. It is too early \nto recommend the ledipasvir + sofosbuvir combination for patients infected with \nother HCV genotypes. The exorbitant price imposed by Gilead endangers public \nhealthcare systems and undermines access to high-quality care.",
"A new validated bioanalytical method based on LC tandem MS has been developed \nfor the simultaneous extraction and determination of sofosbuvir and ledipasvir \nin human plasma using antiviral daclatasvir as an internal standard (IS). \nLiquid-liquid extraction of samples was used for the purification and \npreconcentration of the analytes from a human plasma matrix. Good and consistent \nrecoveries were obtained, with average extraction recoveries of 91.61 and 88.93% \nfor sofosbuvir and ledipasvir, respectively. The chromatographic separation of \nthe three analytes was achieved within only 2.8 min by an isocratic mobile phase \nconsisting of 10 mM ammonium acetate, which was then adjusted to pH 4.0 by \nacetic acid-acetonitrile-0.1% methanolic formic acid (12 + 25 + 63, v/v/v) \nflowing through a C18 Zorbax eclipse plus column (5 μm, 100 × 4.6 mm; Agilent). \nMultiple reaction monitoring transitions were measured in positive ion mode for \nsofosbuvir, ledipasvir, and daclatasvir (IS). A detailed validation of the \nmethod was performed and the standard curves were found to be linear in the \nrange of 0.5 to 2500 and 5 to 2100 ng/mL for sofosbuvir and ledipasvir, \nrespectively, applying weighted (1/X(2)) linear regression. The developed method \nwas applied to the analysis of the two drugs after a single oral administration \nof Harvoni 400/90 mg film-coated tablets containing 400 mg sofosbuvir and 90 mg \nledipasvir to four healthy volunteers.",
"After the introductions of sofosbuvir (Sovaldi) and ledipasvir plus sofosbuvir \n(Harvoni) for the treatment of hepatitis C, employers have become very sensitive \nto new, and especially unforeseen, factors that significantly raise healthcare \ncosts. With the recent launch of the proprotein convertase subtilisin/kexin type \n9 (PCSK9) inhibitors, self-insured and fully insured employers have been seeking \ninformation on this drug class and its potential for off-label use, which could \namount to up to $23 billion in healthcare expenditures, according to a report \nfrom Prime Therapeutics. Based on their approved indications, 0.4% of commercial \nmembers may be eligible to use PCSK9 inhibitors, at a cost of $3.29 per member \nper month. Corporate employers are evaluating their options to manage the new \nexpense associated with the novel PCSK9 inhibitors."
] | nan |
5c6e146a7c78d6947100004c | [
29089721,
28929412
] | train | Which two drugs are included in the MAVYRET pill? | list | MAVYRET pill includes glecaprevir and pibrentasvir. It is used for treatment of hepatitis C infection. | ['glecaprevir', 'pibrentasvir'] | [
"Aminolevulinic acid hydrochloride (Gleolan) for the visualization of malignant \ntissue during surgery; delafloxacin (Baxdela) for certain acute bacterial skin \ninfections; and glecaprevir/pibrentasvir (Mavyret) for chronic HCV infection.",
"A fixed-dose combination tablet of the hepatitis C virus (HCV) NS3/4A protease \ninhibitor (PI) glecaprevir and the HCV NS5A inhibitor pibrentasvir \n[glecaprevir/pibrentasvir; MAVIRET™ (EU); MAVYRET™ (USA)] has been developed by \nAbbVie. Oral glecaprevir/pibrentasvir 300 mg/120 mg (three 100 mg/40 mg tablets) \ntaken once daily has been approved by the EMA for the treatment of all major \ngenotypes (genotypes 1-6) of chronic HCV infection in adults. It has also been \napproved by the US FDA for the treatment of adult patients with chronic HCV \ngenotype 1-6 infection without cirrhosis and with compensated cirrhosis, and for \nthe treatment of adult patients with HCV genotype 1 infection who previously \nhave been treated with a regimen containing either an HCV NS5A inhibitor or an \nNS3/4A PI, but not both. This article summarizes the milestones in the \ndevelopment of glecaprevir/pibrentasvir leading to its first global approval in \nthe EU and subsequent approval in the USA for chronic HCV infection."
] | nan |
589a246178275d0c4a00002b | [
25498373,
27463942,
24561548,
24657685,
23883416,
26839066,
25497244,
25547937,
24281250,
25173541,
22684583,
22572202,
25854636,
21740079,
22298161,
26447668,
22933567,
25294786,
26424386,
25332806,
23859143,
22277459,
23619028,
22449118,
23036896,
23796193,
23026665,
22056819,
23869941,
22787066,
27306620
] | train | Which two drugs were compared in the ARISTOTLE Trial? | list | Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban and warfarin. | ['apixaban', 'warfarin'] | [
"INTRODUCTION AND OBJECTIVES: Cost-effectiveness analysis of apixaban (5 mg twice \ndaily) vs acenocoumarol (5mg/day) in the prevention of stroke in patients with \nnonvalvular atrial fibrillation in Spain.\nMETHODS: Markov model covering the patient's entire lifespan with 10 health \nstates. Data on the efficacy and safety of the drugs were provided by the \nARISTOTLE trial. Warfarin and acenocoumarol were assumed to have therapeutic \nequivalence.\nPERSPECTIVES: The Spanish National Health System and society. Information on the \ncost of the drugs, complications, and the management of the disease was obtained \nfrom Spanish sources.\nRESULTS: In a cohort of 1000 patients with nonvalvular atrial fibrillation, \nadministration of apixaban rather than acenocoumarol would avoid 18 strokes, 71 \nhemorrhages (28 intracranial or major), 2 myocardial infarctions, 1 systemic \nembolism, and 23 related deaths. Apixaban would prolong life (by 0.187 years) \nand result in more quality-adjusted life years (by 0.194 years) per patient. \nWith apixaban, the incremental costs for the Spanish National Health System and \nfor society would be € 2,488 and € 1,826 per patient, respectively. \nConsequently, the costs per life year gained would be € 13,305 and € 9,765 and \nthe costs per quality-adjusted life year gained would be € 12,825 and € 9,412 \nfor the Spanish National Health System and for society, respectively. The \nstability of the baseline case was confirmed by sensitivity analyses.\nCONCLUSIONS: According to this analysis, apixaban may be cost-effective in the \nprevention of stroke in patients with nonvalvular atrial fibrillation compared \nwith acenocoumarol.",
"IMPORTANCE: In the Apixaban for Reduction of Stroke and Other Thromboembolic \nComplications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of \napixaban was 5 mg twice daily; patients with at least 2 dose-reduction \ncriteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL \nor higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is \nknown about patients with 1 dose-reduction criterion who received the 5 mg twice \ndaily dose of apixaban.\nOBJECTIVE: To determine the frequency of 1 dose-reduction criterion and whether \nthe effects of the 5 mg twice daily dose of apixaban on stroke or systemic \nembolism and bleeding varied among patients with 1 or no dose-reduction \ncriteria.\nDESIGN, SETTING, AND PARTICIPANTS: Among 18 201 patients in the ARISTOTLE trial, \n17 322 were included in this analysis. Annualized event rates of stroke or \nsystemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were \nevaluated. Interactions between the effects of apixaban vs warfarin and the \npresence of 1 or no dose-reduction criteria were assessed. The first patient was \nenrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was \ncompleted on January 30, 2011. Data were analyzed from January 2015 to May 30, \n2016.\nMAIN OUTCOMES AND MEASURES: Analysis of major bleeding included events during \nstudy drug treatment. Analysis of stroke or systemic embolism was based on \nintention to treat.\nRESULTS: Of the patients with 1 or no dose-reduction criteria assigned to \nreceive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 \ndose-reduction criterion; these patients had higher rates of stroke or systemic \nembolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, \n1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The \nbenefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with \nwarfarin (n = 8657) on stroke or systemic embolism in patients with 1 \ndose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction \ncriterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). \nSimilarly, the benefit of 5 mg twice daily dose of apixaban compared with \nwarfarin on major bleeding in patients with 1 dose-reduction criterion (HR, \n0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, \n0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen \nfor each dose-reduction criterion and across the spectrum of age, body weight, \ncreatinine level, and creatinine clearance.\nCONCLUSIONS AND RELEVANCE: Patients with atrial fibrillation and isolated \nadvanced age, low body weight, or renal dysfunction have a higher risk of stroke \nor systemic embolism and major bleeding but show consistent benefits with the 5 \nmg twice daily dose of apixaban vs warfarin compared with patients without these \ncharacteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and \nappropriate for patients with only 1 dose-reduction criterion.\nTRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984.",
"AIMS: The risk of stroke in patients with atrial fibrillation (AF) increases \nwith age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced \nthe rate of stroke, death, and bleeding. We evaluated these outcomes in relation \nto patient age.\nMETHODS AND RESULTS: A total of 18 201 patients with AF and a raised risk of \nstroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to \n2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age \n≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to \ncompare outcomes in relation to patient age during 1.8 years median follow-up. \nOf the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were \n≥75 years. The rates of stroke, all-cause death, and major bleeding were higher \nin the older age groups (P < 0.001 for all). Apixaban was more effective than \nwarfarin in preventing stroke and reducing mortality across all age groups, and \nassociated with less major bleeding, less total bleeding, and less intracranial \nhaemorrhage regardless of age (P interaction >0.11 for all). Results were also \nconsistent for the 13% of patients ≥80 years. No significant interaction with \napixaban dose was found with respect to treatment effect on major outcomes.\nCONCLUSION: The benefits of apixaban vs. warfarin were consistent in patients \nwith AF regardless of age. Owing to the higher risk at older age, the absolute \nbenefits of apixaban were greater in the elderly.",
"OBJECTIVES: This study sought to characterize major bleeding on the basis of the \ncomponents of the major bleeding definition, to explore major bleeding by \nlocation, to define 30-day mortality after a major bleeding event, and to \nidentify factors associated with major bleeding.\nBACKGROUND: Apixaban was shown to reduce the risk of major hemorrhage among \npatients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in \nStroke and Other Thromboembolic Events in Atrial Fibrillation) trial.\nMETHODS: All patients who received at least 1 dose of a study drug were \nincluded. Major bleeding was defined according to the criteria of the \nInternational Society on Thrombosis and Haemostasis. Factors associated with \nmajor hemorrhage were identified using a multivariable Cox model.\nRESULTS: The on-treatment safety population included 18,140 patients. The rate \nof major hemorrhage among patients in the apixaban group was 2.13% per year \ncompared with 3.09% per year in the warfarin group (hazard ratio [HR] 0.69, 95% \nconfidence interval [CI]: 0.60 to 0.80; p < 0.001). Compared with warfarin, \nmajor extracranial hemorrhage associated with apixaban led to reduced \nhospitalization, medical or surgical intervention, transfusion, or change in \nantithrombotic therapy. Major hemorrhage followed by mortality within 30 days \noccurred half as often in apixaban-treated patients than in those receiving \nwarfarin (HR 0.50, 95% CI: 0.33 to 0.74; p < 0.001). Older age, prior \nhemorrhage, prior stroke or transient ischemic attack, diabetes, lower \ncreatinine clearance, decreased hematocrit, aspirin therapy, and nonsteroidal \nanti-inflammatory drugs were independently associated with an increased risk.\nCONCLUSIONS: Apixaban, compared with warfarin, was associated with fewer \nintracranial hemorrhages, less adverse consequences following extracranial \nhemorrhage, and a 50% reduction in fatal consequences at 30 days in cases of \nmajor hemorrhage.",
"OBJECTIVE: The Apixaban for Reduction in Stroke and Other Thromboembolic Events \nin Atrial Fibrillation (ARISTOTLE) trial demonstrated that apixaban was \neffective in reducing the risk of stroke and major bleeding in non-valvular \natrial fibrillation (NVAF) patients. Medical cost avoidance studies for oral \nanticoagulants have used warfarin event rates from clinical trials, which may \nnot reflect the real-world (RW) setting. This study aimed to estimate the \ndifference in medical costs associated with apixaban instead of warfarin in RW \nNVAF patients.\nMETHODS: This study selected patients with NVAF diagnosis during 2007-2010 from \na Medco population of US commercial and Medicare health plans. Stroke and major \nbleeding excluding intracranial hemorrhage (MBEIH) were identified using \ndiagnosis codes. Pharmacy claims were used to define warfarin exposure periods. \nRates of stroke and MBEIH were calculated during warfarin exposure. To estimate \nthe absolute risk reduction (ARR) between warfarin and apixaban in RW, the \nrelative risk reductions (RRR) from ARISTOTLE were multiplied by the event rates \nobserved in RW during warfarin exposure. Medical cost reductions associated with \napixaban were calculated by applying the ARR to the 1-year incremental cost for \neach event. Stroke and MBEIH costs were obtained from the literature and \nadjusted to 2011 levels.\nRESULTS: During a patient year, the use of apixaban instead of warfarin resulted \nin medical cost reductions of $493 for stroke and $752 for MBEIH and $1245 for \nthe combined outcome of both events. The medical costs avoided were greater as \nbaseline stroke risk increased.\nCONCLUSION: If RRRs demonstrated in ARISTOTLE persist in RW, the use of apixaban \nwill be associated with lower medical costs vs warfarin. Main limitations of \nthis study were: identification of clinical events using administrative codes \nrather than confirmatory clinical data, inability to evaluate the level of \ninternational normalized ratio (INR) control, and not including INR monitoring \nand drug costs.",
"OBJECTIVE: Atrial fibrillation (AF) is a risk factor for stroke and mortality \nand the prothrombotic state has been linked to inflammation. In this study we \nevaluated the relationship between inflammatory biomarkers at baseline and \nfuture risk of cardiovascular events in the Apixaban for Reduction In Stroke and \nOther Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.\nMETHODS: The ARISTOTLE trial randomised 18,201 patients with AF to apixaban or \nwarfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in \nplasma obtained at randomisation from 14,954 participants, and median follow-up \nwas 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes \nwere analysed by Cox regression adjusted for clinical risk factors and other \ncardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).\nRESULTS: The IL-6 median level was 2.3 ng/L (IQR 1.5-3.9), median CRP level was \n2.2 mg/L (1.0-4.8). IL-6 and CRP were significantly associated with all-cause \nmortality independent of clinical risk factors and other biomarkers (HR (95% CI) \n1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was \nassociated with myocardial infarction, cardiovascular mortality, and major \nbleeding beyond clinical risk factors but not in the presence of cardiovascular \nbiomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory \nbiomarker was associated with stroke/systemic embolism. Risk prediction for \nstroke, death and major bleeding was not improved by IL-6 or CRP when added to \nclinical risk factors and the other cardiovascular biomarkers (NT-proBNP, \ntroponin, GDF-15, cystatin C).\nCONCLUSIONS: In patients with AF on anticoagulation, after accounting for \nclinical risk factors and other biomarkers, biomarkers of inflammation were \nsignificantly associated with an increased risk of mortality. However, there \nwere no associations with the risk of stroke or major bleeding.\nTRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00412984 \npost-results.",
"BACKGROUND: We sought to assess the occurrence of events after blinded study \ndrug discontinuation and transition to open-label vitamin K antagonist (VKA) in \nARISTOTLE.\nMETHODS: At the end of ARISTOTLE, blinded study drug was stopped, and open-label \nVKA was recommended. For patients completing the trial on blinded study drug, a \n2-day bridging period with apixaban or apixaban placebo was recommended (while \nbeginning open-label VKA). Outcomes were assessed during the 30 days after \nstopping blinded study drug.\nRESULTS: Of the 6,809 patients in the apixaban group and 6,588 in the warfarin \ngroup who completed the trial on study drug, there were 21 strokes or systemic \nemboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban \ngroup (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and \n10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), \nwith most of the imbalance between groups being after the first week. Similar \nresults were seen in the first 30 days of the trial where warfarin-naive \npatients starting warfarin had a higher rate of stroke or systemic emboli \n(5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen \nwhen starting apixaban. No similar increase in events with apixaban versus \nwarfarin was seen during temporary or permanent study drug discontinuation \nduring the trial.\nCONCLUSIONS: The excess in thrombotic and bleeding events in the apixaban group \nafter study drug discontinuation appears to be related to an increased risk \nassociated with the initiation of a VKA rather than a direct effect of apixaban. \nWhether ≥2 days of apixaban bridging improves outcomes during VKA transition is \nunknown and deserves further evaluation.",
"Apixaban is one of the new oral anticoagulants, which is prescribed as an \nalternative to vitamin K antagonists (VKAs). Concerns regarding its bleeding \nprofile persist and require further evaluation. Therefore, we conducted a \nmeta-analysis of randomized controlled trials (RCTs) to compare the risks of \nbleeding and all-cause mortality between apixaban and VKAs. The MEDLINE, EMBASE, \nand Cochrane Library of Clinical Trials databases were systematically searched \nfor RCTs comparing the risks of bleeding and all-cause mortality of apixaban \n(2.5 or 5 mg twice daily) with those of VKAs. We included RCTs conducted in \nadults and published in English or French. Data were pooled across RCTs using \nrandom-effects meta-analytical models. Our systematic search identified 5 RCTs \nmeeting our inclusion criteria (n = 24,435). They included patients with atrial \nfibrillation (n = 18,358), total knee replacement surgery (n = 458), and venous \nthromboembolism (n = 5,619). Data pooled across RCTs revealed that apixaban was \nassociated with reduced risks of any bleeding (relative risk [RR] 0.73, 95% \nconfidence interval [CI] 0.59 to 0.90) and a composite of major or clinically \nrelevant nonmajor bleeding (RR 0.60, 95% CI 0.40 to 0.88). Apixaban was also \nassociated with a lower risk of intracranial bleeding (RR 0.42, 95% CI 0.31 to \n0.58) whereas analyses of major and minor bleeding were inconclusive. Moreover, \napixaban was associated with decreased all-cause mortality (RR 0.89, 95% CI 0.81 \nto 0.99) although this finding was driven by the results of the ARISTOTLE trial. \nIn conclusion, our meta-analysis found that apixaban is associated with a lower \nrisk of bleeding than VKAs, providing some reassurance regarding its safety.",
"OBJECTIVE: To determine the cost-effectiveness of apixaban versus warfarin in \npatients with atrial fibrillation (AF) with a moderate to severe risk of stroke, \nfrom an Australian government-perspective.\nMETHODS: A decision-analytic Markov model was constructed to assess the \ncost-effectiveness of apixaban versus warfarin, based on data from the Apixaban \nfor Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial. \nThe model comprised five health states: 'Alive, no major bleeding or stroke', \n'Alive, no major bleeding, post stroke/systemic embolism', 'Alive, post major \nbleeding, no stroke', 'Alive, post-major bleeding and stroke' and 'Dead'. \nDisease cost data was derived from the North-East Melbourne Stroke Incidence \nStudy and the Australian Refined Diagnose Related Groups. Costs of medications \nwere based on data from the Pharmaceutical Benefit Scheme. Utility data was \nderived from published sources, and an annual discount rate of 5% was applied to \ncosts and benefits. The main outcome of interest was incremental \ncost-effectiveness ratios per life year gained (LYG) and quality adjusted life \nyears (QALYs) gained.\nRESULTS: Over 20 years, in the sample of 1000 subjects the model predicted that \ncompared to warfarin, apixaban led to a (discounted) of 0.33 LYG and 0.31 QALYs \ngained, at a net cost of $4,308 per-person. These equated to ICERs of $AUD12, \n914 per LYG and $AUD13, 679 per QALY gained. Probabilistic sensitivity analysis \ndemonstrated that apixaban was cost-effective at 99.0% probability using \nwillingness to pay thresholds of $AUD45 000 per LYG and QALY.\nCONCLUSION: Compared to warfarin, apixaban is likely to represent a \ncost-effective means of preventing stroke-related morbidity and mortality in \npatients with AF.",
"BACKGROUND: The perceived risk of serious bleeding is an obstacle to the use of \noral anticoagulation in East Asia. The efficacy and safety of apixaban in East \nAsian patients with atrial fibrillation are unknown.\nMETHODS: ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation \nrandomized to apixaban 5mg twice daily or warfarin. The efficacy and safety of \napixaban and warfarin among patients recruited from East Asia (n = 1,993) were \ncompared with those recruited from outside East Asia (n = 16,208).\nRESULTS: Compared with warfarin, apixaban resulted in a consistent reduction in \nstroke or systemic embolism in East Asian (hazard ratio [HR] 0.74, 95% CI \n0.50-1.10) and non-East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction \nP = .70). Consistent benefits of apixaban over warfarin were also seen for major \nbleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non-East Asian (HR 0.72, \n95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction \nin major or clinically relevant nonmajor bleeding with apixaban compared with \nwarfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non-East Asian (HR \n0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates \nof intracranial bleeding were seen in East Asian patients with warfarin but not \nwith apixaban.\nCONCLUSIONS: Apixaban resulted in similar reductions in stroke or systemic \nembolism and major bleeding and greater reductions in major or clinically \nrelevant nonmajor bleeding in patients from East Asia. Warfarin is associated \nwith more intracranial bleeding, particularly in patients from East Asia.",
"Stroke prevention in atrial fibrillation (AF) has been challenging over decades, \nmostly due to a number of difficulties associated with oral vitamin K \nantagonists (VKAs), which have been the most effective stroke prevention \ntreatment for a long time. The oral direct thrombin inhibitors (e.g., \ndabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, \napixaban) have emerged recently as an alternative to VKAs for stroke prevention \nin AF. These drugs act rapidly, and have a predictable and stable dose-related \nanticoagulant effect with a few clinically relevant drug-drug interactions. The \nnovel oral anticoagulants are used in fixed doses with no need for regular \nlaboratory monitoring of anticoagulation intensity. However, each of these drugs \nhas distinct pharmacological properties that could influence optimal use in \nclinical practice. The following phase 3 randomized trials with novel oral \nanticoagulants versus warfarin for stroke prevention in AF have been completed: \nthe Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with \ndabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared \nwith vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial \nFibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction \nof Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) \ntrial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to \nprevent Strokes (AVERROES) trial included patients with AF who have failed or \nwere unsuitable for warfarin, and compared apixaban versus aspirin for stroke \nprevention in AF. Overall, apixaban has two large trials for stroke prevention \nin AF showing benefits not only over warfarin, but also over aspirin among those \npatients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban \nwas superior to warfarin in the reduction of stroke or systemic embolism, major \nbleeding, intracranial hemorrhage, and all-cause mortality, with a similar \nreduction in the rate of ischemic stroke and better tolerability. When compared \nwith aspirin in the AVERROES trial, apixaban was associated with more effective \nreduction of stroke, a similar risk of major bleeding, and better tolerability. \nIn this review article, the authors summarize the current knowledge on novel \noral anticoagulants and discuss the clinical aspects of their use for stroke \nprevention in AF, with particular emphasis on apixaban.",
"Collaborators: Granger CB, Wallentin L, Alexander JH, Ansell J, Diaz R, Easton \nJD, Gersh BJ, Hanna M, Horowitz J, Hylek EM, McMurray JJ, Mohan P, Verheugt FW, \nDiaz R, Bahit MC, Aylward P, Amerena J, Huber K, Bartunek J, Avezum A, Ezekowitz \nJA, Dorian P, Lanas F, Lisheng L, Zhu J, Isaza D, Jansky P, Husted S, Harjola \nVP, Steg PG, Hohnloser SH, Keltai M, Pais P, Xavier D, Lewis BS, De Caterina R, \nGoto S, Hermosillo AG, Alings AM, Atar D, Segura L, Ruzyllo W, Vinereanu D, \nVarshavsky S, Golitsyn S, Oh BH, Commerford P, Lopez-Sendon JL, Rosenquist M, \nErol C, McMurray JJ, Parkhomenko A, Flaker G, Garcia D, Pfeffer MA, Diener HC, \nMaggione A, Pocock S, Rouleau JL, Wyse G, Alexander JH, Al-Khatib S, Lopes RD, \nHeld C, Hylek EM, Bushnell C, Terent A, Leonardi S, Subherwal S, Eapen Z, \nVavalle J, Zomorodi A, Kolls B, Berger J, Vergara J, Parikh D, Zia S, Stashenko \nG, Lombardi C, Matthews R, Hagstrom E, Akerblom A, Varenhorst C, Berntsson SG, \nStenborg A, Lundstrom E, Guimaraes H, Flato U, Nacif S, Barros P, Echenique L, \nRodrigues P, Armaganijan L, Lopes AC, Albrecht A, Vico M, Mackinnon I, Vogel D, \nVico M, Gabito A, Cassettari A, Zaidman C, Montaña O, Hrabar A, Jure H, Lastiri \nH, Poy C, Caccavo A, Cuneo C, Colombo H, Rolandi F, Hershson A, Garrido M, \nSanchez A, Bruno ML, Piskorz D, Cuadrado J, Hasbani E, Serra J, Cartasegna L, \nSchygiel P, Muratore C, Marino J, Sosa Liprandi MI, Guerrero RA, Ramos H, \nMercado D, Guzman L, Beneitez C, Estepo J, Torrijos R, Retyk E, Vita N, Luciardi \nH, Casey M, Orlando S, Labarta MB, Santos D, Amerena J, Purnell P, Horowitz J, \nSalem H, Liu A, Zimmet L, Roger S, de Looze F, de Looze F, Lehman R, de Looze F, \nJackson B, Ashby D, Heddle W, Rogers J, Brieger D, Martin P, Cross D, Walters D, \nWaites J, Counsell J, Lowy A, de Looze F, Huber K, Stockenhuber F, Pieske B, \nStriekwold H, Wollaert B, Nachtergaele H, Vijgen J, El Allaf D, Mairesse G, \nBoxho G, De Deyn PP, Vanderheyden M, Semeraro O, Desfontaines P, Leroy J, \nProvenier F, Bruneel B, Vrolix M, Peeters A, Deceuninck O, Saraiva JF, Reis G, \nRossi P, Zimmermann S, Jaber J, Botelho R, Manenti E, Jorge J, Maia L, Leães P, \nVillaça Guimaraes Filho F, Fichino M, De Paola A, Indio do Brasil CK, \nAlbuquerque D, Bodanese L, Matsubara L, Mourilhe Rocha R, Genta P, Meneghelo Z, \nOliveira L, Lorga Filho A, Garbelini B Jr, Oliveira G, Teixeira M, Precoma D, \nPelloso E, Muniz A, Valéria Braile MC, Ueda R, Rabelo Alves A Jr, Pimentel Filho \nP, Zimerman L, Coutinho M, Silveira J, Reis H, Moreira D, Paiva M, Aziz JL, Gois \nJ, Dutra O, Yao L, Syan G, Coutu B, Chehayeb R, Sabe-Affaki G, Fortin C, Borts \nD, Bhargava R, Fell D, Cha J, Pandey A, Boucher P, Sabbah E, Ma P, Talbot P, \nSpence D, Wade A, Green M, Berlingieri J, Vizel S, Chan YK, Blostein M, Talajic \nM, Sterns L, Grondin F, Hruczkowski T, Labonte R, O'Mahony M, Rupka D, Mangat I, \nDowell A, Kelly A, St Maurice F, Henein S, Saunders K, Lasko B, Sami M, \nMacKinnon R, Rizvi Q, O'Keefe D, Ricci J, Gervais B, Hart R, Bose S, Nawaz S, \nConnors S, Winkler L, Boileau M, Healey J, Collette R, Rebane T, Ramjattan B, \nSenior R, Therrien R, Wells P, Raffo C, Cobos J, Potthoff S, Stockins B, \nPincetti C, Corbalan R, Vejar M, Potthoff S, Li W, Zhao S, Chen X, Wu S, Tan H, \nWu S, Qu P, Jiang X, Wei M, Yang X, Li J, Ma S, Gu S, Dai QY, Li L, Yu B, Yin Y, \nWang N, Gao L, Zhou SX, Wang JA, Li ZQ, Bai F, Zhang F, Lu G, Chen Y, Zhang Y, \nJiang D, Zonggui W, Li H, Cao K, Lu Q, Li L, Hu T, Li H, Wang X, Botero R, Reyes \nA, Jaramillo N, Urina M, Velez S, Gomez E, Pava L, Isaza D, Dunaj M, Hudcovic M, \nJerabek O, Brat R, Spinar J, Dedek V, Zidkova E, Podpera I, Cech M, Gorican K, \nMicko M, Stribrna M, Frost L, Torp-Pedersen C, Toftager Larsen C, Tuxen C, May \nO, Pedersen KE, Jensen G, Nielsen T, Nyvad O, Husted S, Gilså Hansen M, Egstrup \nK, Lomholdt J, Skagen K, Joen Jakobsen T, Olsen M, Grande P, Melin J, Tynni M, \nHarjola VP, Strand J, Parikka H, Jääskeläinen T, Corbelli JL, Gosse P, Mirode A, \nMansourati J, Lavabre G, Defaye P, Steg PG, Kahrmann G, Horacek T, Bauer A, \nSpitzer S, Schlegl M, Winkelmann B, Vöhringer HF, Stenzel G, Haverkamp W, \nHarenberg J, Schumacher M, Wunderlich J, Natour M, Rieker W, Gass S, Brachmann \nJ, Jung J, Poppert H, Häge R, Lickfett L, Schoeller R, Goedel-Meinen L, Utech A, \nBuerke M, Maschke M, Haberl R, von Hodenberg E, Griewing B, Schlachetzki F, \nHamer H, Hoch T, Zabel M, Jordan R, Stögbauer F, Hetzel A, Weimar C, Schauerte \nP, Fischer D, Mügge A, Bittersohl A, Mügge A, Lee K, Yu C, Lakatos F, Vértes A, \nKovács A, Takács J, Pálinkás A, Bakai J, Papp A, Illés Á, Tomcsányi J, Szakál I, \nLászló Z, Katona A, Jobbágy L, Keltai K, Dézsi C, Lupkovics G, Cziraki A, \nMohácsi A, Simon K, Gupta S, Agarwal D, Fulwani M, Naik A, Nambiar A, \nChidambaram N, Srinivasasastry B, Joseph J, Padinhare M, Khanna P, Grant P, \nArneja J, Gadkari M, Garg N, Pothineni RB, Sathe S, Ramesh S, Malipeddi B, \nBharani A, Gowdappa HB, Prakash VS, Dharmadhikari A, Bhandari S, Desai N, \nBanerjee S, Ghaisas N, Ramagiri B, Sinha S, Gojanur G, Duggal J, Jain V, Dani S, \nSingh P, Srikanthan V, Puri VK, Gopal R, Viskin S, Shochat M, Hayek T, Reisin L, \nRosenheck S, Lewis B, Zimlichman R, Weiss A, Marmor A, Turgeman Y, Klainman E, \nFrancis A, Lahav M, Omary M, Morris M, Olivieri C, Santonastaso M, Fenici R, Mos \nL, Ghirarduzzi A, De Caterina R, Novo S, Richiardi E, Testa S, Pini M, D'Angelo \nA, Barsotti A, Donati M, Chiariello M, Galli M, Casolo G, Moretti L, Atsushi Y, \nYamamoto K, Goto S, Kihara H, Akihiko T, Saito T, Yoshii H, Sasaki T, Suwa M, \nAdachi S, Usada K, Nakamura Y, Hayashida K, Yamada T, Iwasawa T, Kawase Y, Sugi \nK, Murakami T, Satake K, Iwao T, Maemura K, Koretsune Y, Tsubokou Y, Yamashita \nM, Sato Y, Kouichi F, Yura S, Matsushima A, Iwade K, Kamakura S, Tanaka S, \nMurata H, Yamamoto S, Kobayashi Y, Higashi Y, Shinozaki T, Ikeda H, Hisaoka T, \nNode K, Takagi H, Ong TK, Abidin IZ, Yusof Z, Yusoff K, Maskon O, De los Rios \nIbarra M, Alcocer Gamba M, Lopez Rosas E, Calvo Vargas C, Fajardo Campos P, \nCordero-Cabra JA, JerJes-Sanchez C, Hernandez Santamaria I, Molina L, Olvera \nRuiz R, Arean Martinez C, Gonzalez Guerra J, Morales Gonzalez I, \nCervantes-Escarcega J, Chuquiure-Valenzuela EJ, Riojas C, Gonzalez Hermosillo J, \nGalicia A, Nierop P, Verheugt F, Daniels M, Lok D, Alings A, Scholten M, Plomp \nJ, Derksen R, Bredero A, Zwart P, Schaap A, Michels H, Van der Zwaan C, Hysing \nJ, Elle S, Omland T, Rønnevik P, Øie B, Otterstad JE, Bogale N, Kjærnli T, \nHalvorsen S, Bryhni B, Vikenes K, Cabrera W, Rodriguez A, Chavez C, Gamboa R, \nSegura L, Araoz O, Azanero R, Toce L, Medina F, Bustamante G, Rios Vasquez C, \nZubiate M, Collado F, Morales-Palomares E, Sy R, Morales D, Rogelio G, Abola MT, \nRamos E, Yamamoto M, Collado F, De Leon F, Abelardo N, Kania G, Szpajer M, \nRajzer M, Janion M, Bronisz M, Ruzyllo W, Piepiorka M, Wendland M, Czerski T, \nKorzeniak R, Budaj A, Wawrzynska L, Ogorek M, Miekus P, Tracz W, \nOcicka-Kozakiewicz A, Stepinska J, Kiedrowicz Z, Pasierski T, Kasprzak J, \nGalewicz M, Podogrodzka B, Krauze-Wielicka M, Chmielinski A, \nBoruczkowska-Kaszkowiak A, Piotrowski W, Vinereanu D, Stamate S, Cinteza M, \nTanaseanu CM, Dan GA, Benedek I, Ionescu RM, Lighezan D, Salajan A, Carasca E, \nCapalneanu R, Pop C, Fierbinteanu-Braticevici CG, Zdrenghea DT, Gaita D, Manitiu \nI, Nanea T, Arsenescu Georgescu C, Chizhov P, Kastanayan A, Oleynikov V, \nTreshkur T, Govorin A, Zhelninova T, Barbarash O, Novikova T, Reshetko O, \nSivkova E, Obrezan A, Panchenko E, Popov S, Ivleva A, Zotov D, Gordienko A, \nKamalov G, Chernichka I, Levin A, Zrazhevsky K, Golitsyn S, Shilkina N, Golovach \nA, Filonenko G, Bondarev S, Orlov V, Bragina A, Koziolova N, Svistov A, Shustov \nS, Libov I, Kisliak O, Privalova E, Aleksandrov O, Mazur E, Karpov Y, Belenky D, \nKostenko V, Shubik Y, Ruda M, Arutyunov G, Eltishcheva V, Sidorenko B, Oseshnyuk \nR, Boyarkin M, Pozdnyakov Y, Staxhinskiy N, Sinopalnikov A, Yakushin S, \nKoniakhin A, Yarohno N, Sizova Z, Zadionchenko V, Klimov I, Duplyakov D, \nKanorsky S, Mareev V, Terekhov V, Arkhipov V, Sotnikova T, Yakusevich V, Lesnov \nV, Gordeev I, Gratsiansky N, Shalaev S, Sulimov V, Talibov O, Zemtsovsky E, \nAzarin O, Tan RS, Thorne J, De Jong D, Basson M, van Zyl L, Commerford P, Weich \nH, van Nieuwenhuizen E, Roos J, Kelbe D, Viljoen J, Hong TJ, Oh BH, Park KS, \nJeong MH, Rhim CY, Choi DJ, Sung JH, Kim YN, Bae JH, Tahk SJ, Ryu KH, Kwon SU, \nRho TH, Cha TJ, Shin DG, Álvarez García P, Vida M, Galve E, Bruguera J, Roquer \nJ, Olías de la Cruz F, Paz Bermejo MA, Segura T, Gómez Gómez JH, Ugarriza A, \nPlaza Pérez I, Villacastin J, Bertomeu V, Vargas R, Serena Leal J, Egido Herrero \nJ, Bethencourt González A, Albert X, Gonzalez Juanatey C, Medrano V, Vivancos J, \nAndersson T, Lindholm CJ, Al-Khalili F, Höglund C, Rosenqvist M, Bergström O, \nHerlitz J, Rasmanis G, Johansson L, Christersson C, Fredholm O, Al-Khalili F, \nCallander M, Po H, Pan JP, Tseng CD, Shyu KG, Chu SH, Kultursay H, Gorenek B, \nErol C, Lip G, Albazzaz M, Kadr H, Cohen A, Cooke J, Agarwal A, Brack M, Pye M, \nAnderson M, Dunn F, Wong YK, Glen S, Ford G, Alwail A, Yousef Z, Blagden M, \nMurdoch D, McInnes G, Camm J, Ridsdill Smith W, McMurray JJ, Senior R, Webster \nJ, Dutka D, McClements B, Yousef Z, Levy T, Yogasundram S, Moriarty A, McCullagh \nM, Flather J, Gumbley M, Findlay I, Davies J, Cooke A, Ahsan A, Cannon J, Bakhai \nA, Jacob A, Trouton T, Ajala A, Bartkowiak A, Humiston D, Kufs W, Klancke K, \nJetty P, Gupta D, Nadar V, Yousuf K, Sosa-Suarez G, Gill S, Wukelic M, Mayer N, \nColan D, Haskel E, Grena P, Haught W, Walsh R, Carr K, Tahirkheli N, Jardula M, \nCebe J, Bloom S, Bilazarian S, Gilmore R, Jaffrani N, Goldscher D, Lebowitz A, \nFriedlander I, Stein M, Promisloff S, Magnano A, Dean J, Gerber J, Perloff D, \nCohen Y, Meholick A, Tobin T, Acheatel R, Levanovich P, Ip J, Porterfield J, \nSeshadri N, McKenzie M, Alfieri A, Gazmuri R, Beanblossom B, Van Hamersveld D, \nMcCriskin J, Gelernt M, Bowden W, Sotolongo C, Lang J, Kaatz S, Agnone F, \nHassman D, Flores E, Albrecht F, Hassel C, Quartner J, LaFata J, Bedwell N, \nHerzog W, Amin J, Usedom J, Brockmyre A, Abadier R, Corder C, Marple R, Lovell \nC, Henry W 3rd, Chhabra A, Baker S, Bedoya R, Sandoval R, Nathan M, Garcia D, \nVora K, Sloan S, Kosinski E, Foster R, Salacata A, Weachter R, Bredlau C, Mehta \nP, Russo C, Swint R Sr, Rosenthal S, Bybee K, Peart B, Chaudhuri P, Iteld B, \nStaab M, Rhodes D, Kappler J, Mandviwala M, Niedermaier O, Sofley C, Heiman M, \nGips S, Harris R, East C, Nguyen V, Huling R, Thadani U, Travis D, Maislos F, \nWest M, Castello R, Cohen K, Karlsberg R, Schmedtje J Jr, Gottlieb D, MacKinnon \nA, Noble G, O'Neill P, Roth J, Kobayashi J, Honan M, Hanovich G, Ehrlich S, \nWilson W, Warner A, Rubin A, Rivera E, Leu S, Smith L, Agaiby J, Jan M, Gould R, \nWeiner S, Fleming J, Hemphill J, Parr K, Stoddard M, Curran P, Kurrelmeyer K, \nDesai V, Kereiakes D, Schwarz E, Lillestol M, Vazquez-Tanus J, Vicari R, White \nJ, Shroff R, Fierer R, Vijay N, Hamad A, Kozinn M, Young D, Fenton S, Ouyang P, \nWellford A, Zwerner P, Meyer P, Foley J, Boyle A, Dotani M, Skolnick A, \nRodriguez-Fierro C, Hattler B, Rubin M, Hartley P, Tami L, Ball E, McPherson C, \nEisenberg S, Niazi I, Orlov M, Bachhuber B, Massey C, Phillips W, Mouhayar E, \nGriffin J, Blumberg E, Slabic S, Danisa K, Samal A, Rohrbeck S, McCullough P, \nDohan D, Aycock G, Jones A, Anderson J, Silverman R, Smith W, Mishkel D, \nPatterson N, Moore H, Kabour A, Muttreja M, Jaffrani W, Vidic T, Kent S, Platt \nB, Goldberg R, Kulback S, Patel R, Bazzi A, Goldman S, Roman A, Levin C, \nLachterman B, Chandrashekhar Y, Aisiku I, Powers C, Engeron E, Bernstein R, Shah \nS, Strobel J, Punatar H, Garcia R, Linden D, Al-Mudamgha A, Quick A, Kramer J, \nFeldman G, Stapleton D, Davis M, Graff J, Galizia J, Wassmer P, Chiu D, Ison R, \nCurry K, Finneran M, Solomon A, Schifferdecker B, Seger J, Alexander A, Yates S, \nAshley R Jr, Cordero-Sepulveda J, Cowen P, Ayres T, Kowalski B, Anton S, \nPhillips J, Donovan D, Patel A, Smith R, Updegrove J, Buxton A, Clark D, \nMargolis J, Brooks G, Pernenkil R, Walters J, Richards M, Maccaro P, Pieniek M, \nGarcia Pulido J, Lee CW, Ilvento J, Riff D, Blue B, Welker J, Karunaratne H, \nSantucci P, Vatutin M, Kraiz I, Mostovoy Y, Karpenko O, Tseluyko V, Kononenko L, \nVolkov V, Parkhomenko A, Popik G, Chopey I, Burmak Y, Pavlyk S, Vizir V, Barna \nO, Sychov O, Vykhovanyuk I, Tashchuk V, Khomazjuk I, Andrievskaya S, \nTelyatnikova Z, Bondarchuk O, Netiazhenko V, Seredyuk N, Koval O, Kovalsky I, \nBazylevych A, Lysenko G, Borschivsky M, Yagensky A, Dzyak G, Bereznyakov I, \nRudenko L, Ignatenko G, Amosova K, Voloshyna O, Ivanova L, Tykhonova S, Suprun \nE.",
"BACKGROUND: Atrial fibrillation (AF), the most common cardiac arrhythmia, is a \nmajor risk factor for stroke. Rivaroxaban, an oral factor Xa inhibitor, is \napproved for the prevention of stroke in patients with non-valvular AF. In the \npivotal phase III trial ROCKET AF, rivaroxaban demonstrated non-inferiority \ncompared with warfarin for reducing the risk of stroke or systemic embolism (SE) \nin patients with AF (intention-to-treat analysis), without an increased risk of \nmajor bleeding. Superior efficacy vs. warfarin was achieved while patients were \non study medication. Other direct oral factor Xa inhibitors have completed phase \nIII clinical trials in this indication. Compared with warfarin, apixaban (in the \nARISTOTLE trial) and edoxaban (in the ENGAGE-AF trial) were shown to be superior \nor non-inferior, respectively, for reduction in stroke or SE risk in patients \nwith AF. Baseline stroke risk, as indicated by CHADS2 scores, was lower in \npatients in the ARISTOTLE and ENGAGE-AF trials than in ROCKET AF.\nOBJECTIVES: This review discusses the main findings from ROCKET AF, specifically \nexamining recent subgroup analyses investigating rivaroxaban use across various \npatient types at high risk for adverse outcomes, including those with prior \nstroke or transient ischaemic attack, reduced renal function, prior myocardial \ninfarction, peripheral artery disease, heart failure or patients aged ≥ 75 years \nand those resident in East Asia.\nCONCLUSIONS: These subgroup analyses demonstrate that the treatment effect for \nrivaroxaban vs. warfarin is broadly consistent across a wide range of patient \ngroups, with respect to both efficacy and safety.",
"Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is \nan independent risk factor of potentially catastrophic cardioembolic strokes. AF \npatients are categorized into high-, intermediate-, and low-risk for \nthromboembolic complications using the CHADS(2) or CHA(2)DS(2)-VASc scoring \nsystem. Oral anticoagulation using warfarin has been the standard therapy for \nstroke prevention in intermediate- to high-risk AF patients. However, warfarin \nuse has been limited by several factors such as narrow therapeutic windows, \ndrug-drug and drug-food interactions, and hemorrhagic complications. Rigorous \nresearch evaluated dual antiplatelet therapy of clopidogrel and aspirin \n(acetylsalicylic acid) as a potential alternative to warfarin in the ACTIVE W \ntrial. Dual antiplatelet therapy of clopidogrel and aspirin was found to be \ninferior to warfarin in preventing stroke and systemic embolism with increased \nbleeding risk. Other extensive research has led to the development of new \nantithrombotic agents. Recently, dabigatran etexilate 150 mg twice daily, a \ndirect thrombin inhibitor, was approved by the US FDA for stroke prevention in \npatients with non-valvular AF after it was found to be superior to warfarin in \npreventing thromboembolic events and associated with less bleeding in the RE-LY \ntrial. It was also cost effective when compared with warfarin. Dabigatran can be \nconsidered in high-risk AF patients who are unable or unwilling to comply with \nthe frequent laboratory and clinic visits that are required when receiving \ntreatment with warfarin. Factor Xa inhibitors are another class of new \nanticoagulants that have been developed. Oral rivaroxaban was non-inferior to \nwarfarin in thromboprophylaxis and with similar bleeding in the ROCKET-AF trial \n(HR 0.88; p = 0.117). Apixaban, another factor Xa inhibitor, was superior to \naspirin in reducing stroke and systemic embolism in patients with AF in the \nAVERROES trial (HR 0.45; p < 0.001). The results of the ARISTOTLE trial, which \nis evaluating apixaban against warfarin in ∼18 000 patients with AF, are \nexpected to be available later this year. Edoxaban, another oral factor Xa \ninhibitor, is currently being evaluated against warfarin in the ENGAGE AF-TIMI \n48 trial in ∼20 000 patients with AF. With these new developments, there is a \nnecessity for the clinical practitioner to become familiar with these new and \nupcoming therapies and guidelines. This review provides an overview of the \navailable data regarding the clinical usefulness of these agents.",
"Warfarin has long been considered the gold standard for stroke prevention in \npatients with atrial fibrillation (AF). Recently, three major trials comparing \nthe efficacy and safety of new drugs: a thrombin inhibitor dabigatran and two \ninhibitors of factor Xa - rivaroxaban and apixaban, with that of warfarin, have \nbeen published. The aim of this paper is to present the main results of the \nRE-LY, ROCKET AF and ARISTOTLE trials, compare study populations and outcomes, \nand discuss clinical implications of their results for the long-term \nanticoagulation in patients with nonvalvular AF.",
"BACKGROUND: Comorbid chronic obstructive pulmonary disease (COPD) is associated \nwith poor outcomes among patients with cardiovascular disease. The risks of \nstroke and mortality associated with COPD among patients with atrial \nfibrillation are not well understood.\nMETHODS: We analyzed patients from ARISTOTLE, a randomized trial of 18,201 \npatients with atrial fibrillation comparing the effects of apixaban versus \nwarfarin on the risk of stroke or systemic embolism. Using Cox proportional \nhazards models, we assessed the associations between comorbid COPD and risk of \nstroke or systemic embolism and of mortality, adjusting for treatment \nallocation, smoking history and other risk factors.\nRESULTS: COPD was present in 1950 (10.8%) of 18,134 patients with data on \npulmonary disease history. After multivariable adjustment, COPD was not \nassociated with risk of stroke or systemic embolism (adjusted HR 0.85 [95% CI \n0.60, 1.21], p=0.356). However, COPD was associated with a higher risk of \nall-cause mortality (adjusted HR 1.60 [95% CI 1.36, 1.88], p<0.001) and both \ncardiovascular and non-cardiovascular mortality. The benefit of apixaban over \nwarfarin on stroke or systemic embolism was consistent among patients with and \nwithout COPD (HR 0.92 [95% CI 0.52, 1.63] versus 0.78 [95% CI 0.65, 0.95], \ninteraction p=0.617).\nCONCLUSIONS: COPD was independently associated with increased risk of \ncardiovascular and non-cardiovascular mortality among patients with atrial \nfibrillation, but was not associated with risk of stroke or systemic embolism. \nThe effect of apixaban on stroke or systemic embolism in COPD patients was \nconsistent with its effect in the overall trial population.",
"AIMS: Atrial fibrillation (AF) is common among patients with impaired renal \nfunction. Apixaban, a novel oral anticoagulant with partial renal excretion, was \ncompared with warfarin and reduced the rate stroke, death and bleeding in the \nARISTOTLE trial. We evaluated these outcomes in relation to renal function.\nMETHODS AND RESULTS: Baseline glomerular filtration rate (GFR) was estimated \nusing the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration \n(CKD-EPI) equations as well as cystatin C measurements. According to baseline \nCockcroft-Gault, there were 7518 patients (42%) with an estimated GFR (eGFR) of \n>80 mL/min, 7587 (42%) between >50 and 80 mL/min, and 3017 (15%) with an eGFR of \n≤50 mL/min. The rate of cardiovascular events and bleeding was higher at \nimpaired renal function (≤80 mL/min). Apixaban was more effective than warfarin \nin preventing stroke or systemic embolism and reducing mortality irrespective of \nrenal function. These results were consistent, regardless of methods for GFR \nestimation. Apixaban was associated with less major bleeding events across all \nranges of eGFRs. The relative risk reduction in major bleeding was greater in \npatients with an eGFR of ≤50 mL/min using Cockcroft-Gault {hazard ratio (HR) \n0.50 [95% confidence interval (CI) 0.38-0.66], interaction P = 0.005} or CKD-EPI \nequations [HR 0.48 (95% CI 0.37-0.64), interaction P = 0.003].\nCONCLUSION: In patients with AF, renal impairment was associated with increased \nrisk of cardiovascular events and bleeding. When compared with warfarin, \napixaban treatment reduced the rate of stroke, death, and major bleeding, \nregardless of renal function. Patients with impaired renal function seemed to \nhave the greatest reduction in major bleeding with apixaban.",
"BACKGROUND: Growth differentiation factor 15 (GDF-15), high-sensitivity \ntroponin, and N-terminal pro-brain natriuretic peptide levels are predictive of \ndeath and cardiovascular events in healthy elderly subjects, patients with acute \ncoronary syndrome, and patients with heart failure. High-sensitivity troponin I \nand N-terminal pro-brain natriuretic peptide are also prognostic in patients \nwith atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and \nin addition to clinical characteristics and other biomarkers in patients with \natrial fibrillation.\nMETHODS AND RESULTS: The Apixaban for Reduction in Stroke and Other \nThromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 \npatients with atrial fibrillation to apixaban or warfarin. Biomarkers were \nmeasured at randomization in 14 798 patients. Efficacy and safety outcomes \nduring 1.9 years of follow-up were compared across quartiles of GDF-15 by use of \nCox analyses adjusted for clinical characteristics, randomized treatment, and \nother biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile \nrange, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from \n0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and \nof mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the \nhighest GDF-15 quartile. The prognostic information provided by GDF-15 was \nindependent of clinical characteristics and clinical risk scores. Adjustment for \nthe other cardiac biomarkers attenuated the prognostic value for stroke, whereas \nthe prognostic value for mortality and major bleeding remained. Apixaban \nconsistently reduced stroke, mortality, and bleeding, regardless of GDF-15 \nlevels.\nCONCLUSIONS: GDF-15 is a risk factor for major bleeding, mortality, and stroke \nin atrial fibrillation. The prognostic value for major bleeding and death \nremained even in the presence of N-terminal pro-brain natriuretic peptide and \nhigh-sensitivity troponin I.\nCLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique \nidentifier: NCT00412984.",
"Apixaban is a new oral anticoagulant (NOACs: Novel Oral Anticoagulant), like \ndabigatran, rivaroxaban, and edoxaban. All of them are prescribed to patients \nwith non valvular atrial fibrillation or venous thromboembolism, to replace \nwarfarin, because of the lower probability of bleeding, however they can cause \nbleeding by themselves. Bleeding is an adverse event in patients taking \nanticoagulants. It is associated with a significant increase of morbidity and \nrisk of death. However, these drugs should be used only for the time when \nanticoagulation is strictly required, especially when used for preventing deep \nvein thrombosis. Prolonged use increases the risk of bleeding. In the ARISTOTLE \nTrial Apixaban, compared with warfarin, was associated with a lower rate of \nintracranial hemorrhages and less adverse consequences following extracranial \nhemorrhage. Many physicians still have limited experience with new oral \nanticoagulants and about bleeding risk managment. We reviewed the available \nliterature on extracranial and intracranial bleeding concerning apixaban.",
"OBJECTIVES: A comparative analysis of three major clinical trials with factor Xa \ninhibitor oral anticoagulant (XOAC) drugs versus warfarin in atrial \nfibrillation-Rocket-AF (rivaroxaban), Aristotle (apixaban) and Engage AF Timi 48 \n(edoxaban; two different doses and sets of data)-was carried out.\nMETHODS: Data were extracted from the original reports (study level) and a \nmeta-analysis was carried out.\nRESULTS: When compared with warfarin, XOAC therapy was associated with a \ndecrease in haemorrhagic stroke, with a similar pattern for all regimens and \nmeta-analysis showing a risk ratio of 0.488 (95% CI 0.396 to 0.601). Regarding \ntotal mortality, a favourable pattern was seen for all four regimens and \nmeta-analysis showed a risk ratio of 0.892 (95% CI 0.840 to 0.947). Major \nbleeding and gastrointestinal bleeding provided two examples regarding which \nheterogeneity would seem to exist, when XOAC drugs are compared with warfarin. \nIn what concerns the incidence of myocardial infarction, the primary end point \n(stroke plus systemic embolism) and ischaemic stroke, the situation is less \nclear. These results are inconsistent with a putative 'group effect' for all the \nseven parameters under study, and for some of them it would probably be best to \nlook at each of the individual trial data rather than at the meta-analysis data \n(which seem to lack a clear biological meaning).\nCONCLUSIONS: Apixaban, rivaroxaban and edoxaban have shown interesting effects, \nwhen compared with warfarin in clinical trials, in patients with atrial \nfibrillation, particularly with regard to haemorrhagic stroke and to the \nmortality rate. No other consistent conclusions concerning a putative 'group \neffect' can be reached at the present stage. Concerns regarding adherence to \ntherapy, possible drug interactions, cost and current absence of antidotes may \nbe taken into consideration when choosing an anticoagulant drug.",
"Given the increasing prevalence of atrial fibrillation, the need for safe and \neffective stroke prophylaxis will continue to rise. Warfarin has been around for \nmany years and has proven efficacy in preventing stroke, but it has major \nlimitations due to its variable dosing, food and drug interactions, and \nrequirement for regular monitoring. Newer agents which include dabigatran, \nrivaroxaban, and apixaban have recently or will soon be available and may \nprovide an improved efficacy in stroke prevention, an improved safety profile, \nand improved user-friendliness. Dabigatran was the first of the agents to be \nwidely available, and in the RE-LY study, dabigatran (150 mg dose) showed \nsuperiority to warfarin in preventing ischemic stroke and a significant \nreduction in intracranial bleeding. Rivaroxaban was studied in the ROCKETAF \ntrial, and with once daily dosing, it showed noninferiority to warfarin in \npreventing stroke with a significant reduction in intracranial bleeding. The \nARISTOTLE trial showed apixaban was superior to warfarin for stroke prevention, \nsignificantly reduced all major bleeding, and resulted in a significant \nreduction in all-cause mortality. While all three trials have important \nlimitations, they were very large randomized trials with more than 14,000 \npatients each and show a clear overall net clinical benefit when compared with \nwarfarin. Key features of the drugs as well as an individual's preferences and \nstability on warfarin will help guide the ultimate drug choice for any given \npatient, but these newer anticoagulant agents are likely to usher in a new era \nin stroke prevention in atrial fibrillation.",
"Anticoagulant therapy, known as warfarin, has been underused despite its marked \nbenefit from embolic prevention. The intricate maintenance has made physicians \nconstrained the use of warfarin for the many decades. Facing the 21(st) century, \nseveral new anticoagulants which inhibit single coagulant factor, such as \nactivated factor X (Xa) or activated factor II (thrombin), has been developed. \nWe now have selective thrombin inhibitor, dabigatran, already rolled out in \nclinical practice around the world. Among these drugs, four new Xa inhibitors \nare in final developing stage. This article reviewed the current status of new \nXa inhibitors. Rivaroxaban leads the other Xa inhibitors in distribution. The \nphase III clinical study called ROCKET AF study had been completed and recently \npublished. Statistical non-inferiority was clearly established compared to \nregular warfarin therapy. The Japanese rolled J-ROCKET AF study with 1,000 \npatients and the usage of reduced dose of rivaroxaban has made a similar outcome \nand safety end points compared to the initial ROCKET AF study. ARISTOTLE study, \na phase III clinical study of apixaban has also been finished this year and will \nbe presented soon. A phase III study of using edoxaban, a Japanese manufactured \nXa inhibitor, named ENGAGE AF-TIMI 48 will be completed by next year. Darexaban, \nanother Japan-made Xa inhibitor is in its preparation of phase III trial \nfollowing favorable results of its late phase II study (OPAL-2). Having every \ntrial with its favorable outcome, multiple alternatives of Xa inhibitors will be \nout in practice in no distant future. In addition, we must be aware to have a \ndeliberate evaluation for each result, even pharmacological profiles of each Xa \ninhibitors with a 12 hour half-life period shows similarity, the difference in \ntwice-daily dosing with once a day, or the difference in severity of patients' \natrial fibrillation risk factor each trial contains might affect the results of \nphase III trials.",
"Alternative anticoagulants to warfarin (dabigatran, rivaroxaban, and apixaban) \nare becoming available for the prevention of thromboembolic stroke in atrial \nfibrillation (AF), but there is a lack of information on their comparative \neffectiveness. Using a discrete event simulation method adopting a lifetime \nhorizon of analysis, we made an indirect comparison of the RE-LY, ROCKET-AF, and \nARISTOTLE trial results for AF patients in the US population. Over a lifetime, \napixaban, dabigatran, and rivaroxaban accrued 0.130 (95% central range (CR) \n-0.030 to 0.264), 0.106 (95% CR -0.048 to 0.248), and 0.095 (95% CR -0.052 to \n0.242) more quality-adjusted life-years (QALYs), respectively, than warfarin, \nwith apixaban having a 55% probability of accruing the highest total QALYs. In \nthe absence of a definitive trial, and acknowledging the limitations of an \nindirect comparison, the available evidence suggests apixaban to be the most \neffective anticoagulant.",
"OBJECTIVE: The randomized clinical trials, RE-LY, ROCKET-AF, and ARISTOTLE, \ndemonstrate that the novel oral anticoagulants (NOACs) are effective options for \nstroke prevention among non-valvular atrial fibrillation (AF) patients. This \nstudy aimed to evaluate the medical cost reductions associated with the use of \nindividual NOACs instead of warfarin from the US payer perspective.\nMETHODS: Rates for efficacy and safety clinical events for warfarin were \nestimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE \ntrials, and event rates for NOACs were determined by applying trial hazard \nratios or relative risk ratios to such weighted averages. Incremental medical \ncosts to a US health payer of an AF patient experiencing a clinical event during \n1 year following the event were obtained from published literature and inflation \nadjusted to 2010 cost levels. Medical costs, excluding drug costs, were \nevaluated and compared for each NOAC vs warfarin. Sensitivity analyses were \nconducted to determine the influence of variations in clinical event rates and \nincremental costs on the medical cost reduction.\nRESULTS: In a patient year, the medical cost reduction associated with NOAC \nusage instead of warfarin was estimated to be -$179, -$89, and -$485 for \ndabigatran, rivaroxaban, and apixaban, respectively. When clinical event rates \nand costs were allowed to vary simultaneously, through a Monte Carlo simulation, \nthe 95% confidence interval of annual medical costs differences ranged between \n-$424 and +$71 for dabigatran, -$301 and +$135 for rivaroxaban, and -$741 and \n-$252 for apixaban, with a negative number indicating a cost reduction. Of the \n10,000 Monte-Carlo iterations 92.6%, 79.8%, and 100.0% were associated with a \nmedical cost reduction >$0 for dabigatran, rivaroxaban, and apixaban, \nrespectively.\nCONCLUSIONS: Usage of the NOACs, dabigatran, rivaroxaban, and apixaban may be \nassociated with lower medical (excluding drug costs) costs relative to warfarin, \nwith apixaban having the most substantial medical cost reduction.",
"BACKGROUND: The Apixaban for Reduction in Stroke and Other Thromboembolic Events \nin Atrial Fibrillation (ARISTOTLE) trial showed that apixaban is better than \nwarfarin at prevention of stroke or systemic embolism, causes less bleeding, and \nresults in lower mortality. We assessed in this trial's participants how results \ndiffered according to patients' CHADS(2), CHA(2)DS(2)VASc, and HAS-BLED scores, \nused to predict the risk of stroke and bleeding.\nMETHODS: ARISTOTLE was a double-blind, randomised trial that enrolled 18,201 \npatients with atrial fibrillation in 39 countries. Patients were randomly \nassigned apixaban 5 mg twice daily (n=9120) or warfarin (target international \nnormalised ratio 2·0-3·0; n=9081). The primary endpoint was stroke or systemic \nembolism. The primary safety outcome was major bleeding. We calculated CHADS(2), \nCHA(2)DS(2)VASc, and HAS-BLED scores of patients at randomisation. Efficacy \nanalyses were by intention to treat, and safety analyses were of the population \nwho received the study drug. ARISTOTLE is registered with ClinicalTrials.gov, \nnumber NCT00412984.\nFINDINGS: Apixaban significantly reduced stroke or systemic embolism with no \nevidence of a differential effect by risk of stroke (CHADS(2) 1, 2, or ≥3, p for \ninteraction=0·4457; or CHA(2)DS(2)VASc 1, 2, or ≥3, p for interaction=0·1210) or \nbleeding (HAS-BLED 0-1, 2, or ≥3, p for interaction=0·9422). Patients who \nreceived apixaban had lower rates of major bleeding than did those who received \nwarfarin, with no difference across all score categories (CHADS(2), p for \ninteraction=0·4018; CHA(2)DS(2)VASc, p for interaction=0·2059; HAS-BLED, p for \ninteraction=0·7127). The relative risk reduction in intracranial bleeding tended \nto be greater in patients with HAS-BLED scores of 3 or higher (hazard ratio [HR] \n0·22, 95% CI 0·10-0·48) than in those with HAS-BLED scores of 0-1 (HR 0·66, \n0·39-1·12; p for interaction=0·0604).\nINTERPRETATION: Because apixaban has benefits over warfarin that are consistent \nacross patient risk of stroke and bleeding as assessed by the CHADS2, \nCHA2DS2VASc, and HAS-BLED scores, these scores might be less relevant when used \nto tailor apixaban treatment to individual patients than they are for warfarin. \nFurther improvement in risk stratification for both stroke and bleeding is \nneeded, particularly for patients with atrial fibrillation at low risk for these \nevents.\nFUNDING: Bristol-Myers Squibb and Pfizer.",
"BACKGROUND: Clinical event rates may differ among patients treated in the real \nworld (RW) compared to randomized controlled trials (RCTs). When translating the \nefficacy of new treatments to RW, the relative risk reductions (RRRs) from RCTs \nmay produce different absolute risk reductions in RW.\nOBJECTIVE: To estimate the absolute effect of apixaban on stroke and major \nbleeding (MB) rates in a RW non-valvular atrial fibrillation (NVAF) population.\nMETHODS: NVAF patients were selected during 2007-2010 from a population of U.S. \ncommercial and Medicare health plans using the Medco claims database. Pharmacy \nclaims were used to define warfarin exposure periods. Stroke and MB were \nidentified using diagnosis codes. RW event rates were calculated during periods \nof warfarin exposure. The numbers of stroke and MB events estimated to be \navoided in RW with apixaban versus warfarin were calculated by applying RRRs \nfrom the ARISTOTLE trial to RW rates from the Medco database. The Medco data did \nnot contain information for patients receiving apixaban as it was not on the \nmarket at the time of analysis.\nRESULTS: Stroke and MB rates among RW NVAF patients during warfarin exposure \nwere higher compared with event rates in patients treated with warfarin in \nARISTOTLE (stroke: 5.29 vs. 1.51 per 100 person years (PYs); MB: 10.78 vs. 3.09 \nper 100 PYs). If RRRs from trials persist in RW, apixaban vs. warfarin would \nresult in greater absolute risk reductions (ARRs) and a lower number needed to \ntreat (NNT) in RW vs. ARISTOTLE (stroke: 91 vs. 313; MB: 30 vs. 105).\nCONCLUSION: The impact of apixaban, as an alternative to warfarin in RW may be \ngreater than in RCTs. The NNT with apixaban versus warfarin in RW may be lower \nversus ARISTOTLE if RRRs from the trial persists in RW and if baseline stroke \nand MB rates among RW patients are higher compared to trial participants.",
"The incidence and prevalence of atrial fibrillation are quickly increasing, \nmainly due to the ageing of the population. Atrial fibrillation is, to date, a \nproblem of public health. Atrial fibrillation is associated to a five-fold risk \nof stroke, which may be identified by score risks, such as CHADS(2) score. The \nclassical antithrombotic treatment of atrial fibrillation is based on vitamin K \nantagonists. Trials made in the 90's have clearly shown that vitamin K \nantagonists were able to decrease stroke risk by about 60%. New oral \nanticoagulants are now available on the market to treat patients with atrial \nfibrillation. These drugs are dabigatran which has demonstrated an interest in \nthe RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa \nhave also demonstrated an interest : rivaroxaban in the ROCKET AF trial and \napixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future \nthese drugs will have a major place in the armamentarium used to treat patients \nwith atrial fibrillation. In all these trials a decrease in intra cranial \nhaemorrhages has been demonstrated. In the everyday practice it will be \nnecessary to be very cautious in patients with impaired renal function, as all \nthese drugs are eliminated by kidneys.",
"The objective of this review is to summarize data from the Apixaban for \nReduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation \n(ARISTOTLE) and Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial \nFibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist \nTreatment (AVERROES) trials of apixaban for stroke prevention in patients with \natrial fibrillation (AF). The ARISTOTLE trial compared apixaban with warfarin in \n18 201 patients with AF and ≥ 1 additional risk factor for stroke. The AVERROES \ntrial compared apixaban with aspirin in 5599 patients with AF who were at \nincreased risk of stroke and for whom vitamin K antagonists were unsuitable. In \nARISTOTLE, apixaban reduced the risk of stroke or systemic embolism by 21% \ncompared with warfarin (1.27% vs 1.60% per year; hazard ratio, 0.79; 95% \nconfidence interval, 0.66-0.95). The reduction was significant and demonstrated \nthe superiority of apixaban over warfarin for the primary outcome of preventing \nstroke or systemic embolism (P = 0.01 for superiority). Apixaban also reduced \nall-cause mortality by 11% (P = 0.047) and major bleeding by 31% (P < 0.001) \ncompared with warfarin. The benefits of apixaban observed in ARISTOTLE are \nfurther supported by the results from AVERROES, which demonstrated a 55% \nreduction in the risk of stroke or systemic embolism compared with aspirin. Risk \nof major bleeding was not significantly different between apixaban and aspirin. \nSubgroup analyses in both trials demonstrated that the effects of apixaban are \nhighly consistent across various patient subpopulations. Discontinuation of \nstudy medication was significantly lower with apixaban than with either warfarin \nin ARISTOTLE or aspirin in AVERROES. Apixaban is the first new oral \nanticoagulant that has been shown to be superior to warfarin in reducing stroke \nor systemic embolism, all-cause mortality, and major bleeding in patients with \nAF. Moreover, in patients with AF who are considered unsuitable for warfarin \ntherapy, apixaban was more effective than aspirin for stroke prevention and had \na similar rate of major bleeding.",
"OBJECTIVES: Based on clinical trials the oral anticoagulants (OACs) apixaban, \ndabigatran, and rivaroxaban are efficacious for reducing stroke risk for \nnon-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, \nthis study evaluated the medical costs for clinical events among NVAF patients \n≥75 and <75 years of age treated with individual OACs vs warfarin.\nMETHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., \nclinical events) among NVAF patients receiving warfarin or each of the OACs were \ndetermined for NVAF populations aged ≥75 years and <75 years of age from the OAC \nvs warfarin trials. One-year incremental costs among patients with clinical \nevents were obtained from published literature and inflation adjusted to 2010 \ncosts. Medical costs, excluding medication costs, for clinical events associated \nwith each OAC and warfarin were then estimated and compared.\nRESULTS: Among NVAF patients aged ≥75, compared to warfarin, use of either \napixaban or rivaroxaban was associated with a reduction in medical costs per \npatient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was \nassociated with increased medical costs of $180 per patient year. Among NVAF \npatients <75 years of age medical costs per patient year were estimated to be \nreduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban, \nrespectively, in comparison to warfarin.\nLIMITATIONS: This economic analysis was based on clinical trial data and, \ntherefore, the direct application of the results to routine clinical practice \nwill require further assessment.\nCONCLUSIONS: Difference in medical costs between OAC and warfarin treated NVAF \npatients vary by age group and individual OACs. Although reductions in medical \ncosts for NVAF patients aged ≥75 and <75 were observed for those using either \napixaban or rivaroxaban vs warfarin, the reductions were greater per patient \nyear for both the older and younger NVAF populations using apixaban.",
"BACKGROUND: Dabigatran, an oral thrombin inhibitor, and rivaroxaban and \napixaban, oral factor Xa inhibitors, have been found to be safe and effective in \nreducing stroke risk in patients with atrial fibrillation. We sought to compare \nthe efficacy and safety of the 3 new agents based on data from their published \nwarfarin-controlled randomized trials, using the method of adjusted indirect \ncomparisons.\nMETHODS AND RESULTS: We included findings from 44 535 patients enrolled in 3 \ntrials of the efficacy of dabigatran (Randomized Evaluation of Long-Term \nAnticoagulation Therapy [RELY]), apixaban (Apixaban for Reduction in Stroke and \nOther Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]), and rivaroxaban \n(Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K \nAntagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation \n[ROCKET-AF]), each compared with warfarin. The primary efficacy end point was \nstroke or systemic embolism; the safety end point we studied was major \nhemorrhage. To address a lack of comparability between trial populations caused \nby the restriction of ROCKET-AF to high-risk patients, we conducted a subgroup \nanalysis in patients with a CHADS(2) score ≥3. We found no statistically \nsignificant efficacy differences among the 3 drugs, although apixaban and \ndabigatran were numerically superior to rivaroxaban. Apixaban produced \nsignificantly fewer major hemorrhages than dabigatran and rivaroxaban.\nCONCLUSIONS: An indirect comparison of new anticoagulants based on existing \ntrial data indicates that in patients with a CHADS(2) score ≥3 dabigatran 150 \nmg, apixaban 5 mg, and rivaroxaban 20 mg resulted in statistically similar rates \nof stroke and systemic embolism, but apixaban had a lower risk of major \nhemorrhage compared with dabigatran and rivaroxaban. Until head-to-head trials \nor large-scale observational studies that reflect routine use of these agents \nare available, such adjusted indirect comparisons based on trial data are one \ntool to guide initial therapeutic choices.",
"OBJECTIVE: To determine whether the treatment effect of apixaban versus \nwarfarin differs with increasing numbers of concomitant drugs used by patients \nwith atrial fibrillation.\nDESIGN: Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban \nfor reduction in stroke and other thromboembolic events in atrial \nfibrillation)-a multicentre, double blind, double dummy trial that started in \n2006 and ended in 2011.\nPARTICIPANTS: 18 201 ARISTOTLE trial participants.\nINTERVENTIONS: In the ARISTOTLE trial, patients were randomised to either 5 mg \napixaban twice daily (n=9120) or warfarin (target international normalised ratio \nrange 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into \ngroups according to the number of concomitant drug treatments used at baseline \n(0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years.\nMAIN OUTCOME MEASURES: Clinical outcomes and treatment effects of apixaban \nversus warfarin (adjusted for age, sex, and country).\nRESULTS: Each patient used a median of six drugs (interquartile range 5-9); \npolypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of \nconcomitant drugs were used in older patients, women, and patients in the United \nStates. The number of comorbidities increased across groups of increasing \nnumbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients \ntreated with drugs that interact with warfarin or apixaban. Mortality also rose \nsignificantly with the number of drug treatments (P<0.001), as did rates of \nstroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for \n0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 \nper 100 patient years, respectively). Relative risk reductions in stroke or \nsystemic embolism for apixaban versus warfarin were consistent, regardless of \nthe number of concomitant drugs (Pinteraction=0.82). A smaller reduction in \nmajor bleeding was seen with apixaban versus warfarin with increasing numbers of \nconcomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) \ndrugs for warfarin or apixaban had similar outcomes and consistent treatment \neffects of apixaban versus warfarin.\nCONCLUSIONS: In the ARISTOTLE trial, three quarters of patients had \npolypharmacy; this subgroup had an increased comorbidity, more interacting \ndrugs, increased mortality, and higher rates of thromboembolic and bleeding \ncomplications. In terms of a potential differential response to anticoagulation \ntherapy in patients with atrial fibrillation and polypharmacy, apixaban was more \neffective than warfarin, and is at least just as safe.Trial \nregistration ARISTOTLE trial, ClinicalTrials.gov NCT00412984."
] | ['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D017428'] |
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] | train | Which two genes are implicated in Juvenile polyposis syndrome? | list | Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation being identified in about 40-50% of patients. | ['SMAD4', 'BMPR1A'] | [
"Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary \ndisorder, characterized by multiple juvenile polyps in the gastrointestinal \ntract and an increased risk of colorectal cancer. JPS is most frequently caused \nby mutations in the SMAD4 or BMPR1A genes. Herein, we report a child with \njuvenile polyposis syndrome (JPS) with a novel mutation in the SMAD4 gene. An \n8-year-old boy presented with recurrent rectal bleeding and was found to have \nmultiple polyps in the entire colon. The histology of the resected polyps was \nconsistent with juvenile polyps. Subsequent genetic screening revealed a novel \nmutation in SMAD4, exon 5 (p.Ser144Stop). To the best of our knowledge, this \nmutation has not been reported before. Offering genotypic diagnosis for patients \nwith JPS is an important step for strategic plan of management.",
"BACKGROUND: Menetrier's disease (MD) is a rare disease with unknown aetiology, \ncharacterized by hypertrophic folds within the fundus and body of the stomach.\nAIMS: We investigated mutations of the candidate genes SMAD4, BMPR1A, TGF-α, and \nPDX1 within a family with MD.\nMETHODS: A large 4-generation family with MD was identified. This family had 5 \ncases of MD, 1 case of MD and juvenile polyposis syndrome (JPS) and 3 cases of \nJPS. Participants provided saliva for DNA extraction and completed a health \nquestionnaire designed to assess conditions that may be found in patients with \nMD. Following pedigree analysis, we sequenced the coding regions of the SMAD4 \nand BMPR1A genes and the regulatory regions of the TGF-α and PDX1 genes in \naffected and non-affected family members.\nRESULTS: No mutations were identified in the sequenced regions of BMPR1A, TGF-α, \nor PDX1. A dominant 1244_1247delACAG mutation of SMAD4 was identified in each of \nthe subjects with JPS as well as in each of the subjects with MD. Although this \nmutation segregated with disease, there were also unaffected/undiagnosed \ncarriers.\nCONCLUSION: The 1244_1247delACAG mutation of SMAD4 is the cause of JPS and the \nlikely cause of MD in a large family initially diagnosed with MD.",
"BACKGROUND: Juvenile polyposis syndrome is a dominant GI polyposis syndrome \ndefined by ≥ 5 GI juvenile polyps or ≥ 1 juvenile polyps with a family history \nof juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of \nindividuals. Hereditary hemorrhagic telangiectasia is a dominant disorder \ncharacterized by epistaxis, visceral arteriovenous malformations, and \ntelangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 \ncriteria including clinical manifestations or a family history, are present. A \njuvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has \npreviously been reported in 22% of patients with juvenile polyposis due to a \nSMAD4 mutation.\nOBJECTIVE: Our objective was to determine the prevalence and clinical \nmanifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in \nour juvenile polyposis SMAD4 patients.\nDESIGN, PATIENTS, AND SETTING: This was a cohort study of juvenile polyposis \npatients in our inherited colon cancer registries. Hereditary hemorrhagic \ntelangiectasia manifestations were obtained from medical records, patient \ncontact, and/or prospective hereditary hemorrhagic telangiectasia screening. The \nCuracao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia \n(≥ 3 criteria diagnostic; 2 criteria suspect of).\nMAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary \nhemorrhagic telangiectasia in juvenile polyposis SMAD4 patients.\nRESULTS: Forty-one juvenile polyposis families were identified. Genetic testing \nwas available for individuals within 18 families. SMAD4 mutations were found in \n21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary \nhemorrhagic telangiectasia and 14% were suspected of having hereditary \nhemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in \nour overlap patients. Symptomatic and subclinical arteriovenous malformations \nwere noted near universally.\nLIMITATIONS: There was a single, tertiary referral center.\nCONCLUSIONS: Nearly all juvenile polyposis SMAD4 patients have the overlap \nsyndrome. The clinical implications and need for hereditary hemorrhagic \ntelangiectasia screening are important factors for genetic testing in juvenile \npolyposis. Health care providers must be cognizant of the juvenile \npolyposis-hereditary hemorrhagic telangiectasia overlap syndrome and the \nimplications for management of these patients.",
"Juvenile polyposis syndrome is an autosomal dominant inherited disorder \ncharacterized by multiple juvenile polyps arising in the gastrointestinal tract \nand an increased risk of gastrointestinal cancers, specifically colon cancer. \nBMPR1A and SMAD4 germline mutations have been found in patients with juvenile \npolyposis syndrome. We identified a BMPR1A mutation, which involves a \nduplication of coding exon 3 (c.230+452_333+441dup1995), on multiple ligation \ndependent probe amplification in a patient with juvenile polyposis syndrome. The \nmutation causes a frameshift, producing a truncated protein (p.D112NfsX2). \nTherefore, the mutation is believed to be pathogenic. We also identified a \nduplication breakpoint in which Alu sequences are located. These results suggest \nthat the duplication event resulted from recombination between Alu sequences. To \nour knowledge, partial duplication in the BMPR1A gene has not been reported \npreviously. This is the first case report to document coding exon 3 duplication \nin the BMPR1A gene in a patient with juvenile polyposis syndrome.",
"Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder \npredisposing to gastrointestinal hamartomatous polyps and cancer with a \npathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about \n40-50% of patients. Little is known, however, about the occurrence and nature of \nsomatic alterations (2nd-hit) in SMAD4-/BMPR1A-related juvenile polyps. In this \nstudy, we screened 25 polyps from three patients carrying either a pathogenic \nSMAD4 (c.1244-1247delACAG) or BMPR1A (c.583C>T; p.Gln195*) germline mutation for \nsomatic alterations. The SMAD4-related polyps were also analyzed for SMAD4 \nprotein expression by immunohistochemistry. Despite comprehensive screening for \nloss of heterozygosity (LOH), mutations in the coding sequence, chromosomal \nrearrangements, and promoter methylation, no somatic alterations could be \nidentified in 14 SMAD4-related polyps. SMAD4 protein expression, however, was \nlost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, \nthe epithelial and stromal, compartments. In the BMPR1A-related polyps, five out \nof nine (56%) displayed LOH. Further analysis of selected polyps revealed that \nLOH was gene copy number neutral and had occurred in the epithelial compartment. \nThe heterogeneity of genetic mutations and protein expression levels indicates \nthat different modes of gene inactivation can be operational in SMAD4- and \nBMPR1A-related polyp formation. Our observation, that about half of \nBMPR1A-related polyps displayed LOH, predominantly in the epithelial \ncompartment, is compatible with BMPR1A acting as a tumour suppressor gene. \nStill, it remains to be determined whether juvenile polyp development generally \nrequires loss of BMPR1A expression or, as observed in some SMAD4-related polyps, \ncan occur despite normal protein expression.",
"We describe a patient with a severe juvenile polyposis phenotype, due to a de \nnovo deletion of chromosome 10q22.3-q24.1. He was initially diagnosed with \nJuvenile polyposis syndrome (JPS) at age four after presenting with hematochezia \ndue to multiple colonic juvenile polyps. He then re-presented at 23 years with \nrecurrent hematochezia from juvenile polyps in his ileoanal pouch. He is one of \nthe earliest reported cases of JPS associated with a large deletion of \nchromosome 10. Since his initial diagnosis of JPS further studies have confirmed \nan association between JPS and mutations in BMPR1A in chromosome band 10q23.2, \nwhich is in close proximity to PTEN. Mutations in PTEN cause Cowden syndrome \n(CS) and other PTEN hamartoma tumor syndromes. Due to the chromosome 10 deletion \ninvolving contiguous portions of BMPR1A and PTEN in our patient, he may be at \nrisk for CS associated cancers and features, in addition to the polyps \nassociated with JPS. This case presents new challenges in developing appropriate \nsurveillance algorithms to account for the risks associated with each syndrome \nand highlights the importance of longitudinal follow-up and transitional care \nbetween pediatric and adult gastroenterology for patients with hereditary \npolyposis syndromes.",
"Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized \nby multiple distinct juvenile polyps in the gastrointestinal tract and an \nincreased risk of colorectal cancer. The cumulative life-time risk of colorectal \ncancer is 39% and the relative risk is 34. Juvenile polyps have a distinctive \nhistology characterized by an abundance of edematous lamina propria with \ninflammatory cells and cystically dilated glands lined by cuboidal to columnar \nepithelium with reactive changes. Clinically, juvenile polyposis syndrome is \ndefined by the presence of 5 or more juvenile polyps in the colorectum, juvenile \npolyps throughout the gastrointestinal tract or any number of juvenile polyps \nand a positive family history of juvenile polyposis. In about 50%-60% of \npatients diagnosed with juvenile polyposis syndrome a germline mutation in the \nSMAD4 or BMPR1A gene is found. Both genes play a role in the BMP/TGF-beta \nsignalling pathway. It has been suggested that cancer in juvenile polyposis may \ndevelop through the so-called \"landscaper mechanism\" where an abnormal stromal \nenvironment leads to neoplastic transformation of the adjacent epithelium and in \nthe end invasive carcinoma. Recognition of this rare disorder is important for \npatients and their families with regard to treatment, follow-up and screening of \nat risk individuals. Each clinician confronted with the diagnosis of a juvenile \npolyp should therefore consider the possibility of juvenile polyposis syndrome. \nIn addition, juvenile polyposis syndrome provides a unique model to study \ncolorectal cancer pathogenesis in general and gives insight in the molecular \ngenetic basis of cancer. This review discusses clinical manifestations, \ngenetics, pathogenesis and management of juvenile polyposis syndrome.",
"Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal \nvascular structures that may present as epistaxis, telangiectasias, and/or \narteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and \nSMAD4) are members of the TGFβ pathway. Other syndromes associated with \nabnormalities in TGFβ signaling include Marfan syndrome, Loeys-Dietz syndrome \nand related disorders. These disorders have aortic disease as a prominent \nfinding. While there are case reports of patients with HHT and aortopathy \n(dilatation/aneurysm, dissection, and rupture), this has not been systematically \ninvestigated. We conducted a retrospective chart review to determine the \nprevalence of aortopathy in an HHT cohort. Patients from a single institution \nwere identified who met the Curacao Criteria for a clinical diagnosis of HHT \nand/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. \nTwo-dimensional echocardiograms were reviewed by a single pediatric \ncardiologist, and data were collected on demographics, genotype, HHT features, \naortic root measurements, past medical history, and family history. Z scores and \nnomograms were utilized to identify abnormal results. Twenty-six patients from \n15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were \nincluded in the analysis. Aortopathy was found in 6/26 (23%) patients; all had \nSMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence \nof aortopathy. These data suggest that aortopathy could be part of the spectrum \nof SMAD4-induced HHT manifestations. Routine aortic imaging, including \nmeasurements of the aorta, should be considered in patients with SMAD4 mutations \nto allow for appropriate medical and surgical recommendations.",
"Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to the \noccurrence of hamartomatous polyps in the gastrointestinal tract. Diagnosis of \nJPS is based on the occurrence of numerous colon and rectum polyps or any number \nof polyps with family history and, in the case of juvenile polyps, their \noccurrence also outside the large intestine. The JPS is caused by mutations in \nSMAD4 and BMPR1A. Products of the SMAD4 gene are involved in signal transduction \nin the transforming growth factor β pathway and BMPR1A protein is a receptor \nbelonging to the family of transmembrane serine/threonine kinases. Both proteins \nare responsible for processes determining appropriate development of colonic \nmucosa. The JPS belongs to the group of hamartomatous polyposes. The \nhamartomatous polyposis syndromes constitute a group of diseases in which \nmanifestations differ slightly and only molecular diagnostics gives the \npossibility of verifying the clinical diagnosis.",
"Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder \ncharacterized by the development of multiple hamartomatous polyps in the \ngastrointestinal tract. Polyps are most common in the colorectum (98% of \npatients) and the stomach (14%). Causative mutations for JPS have been \nidentified in two genes to date, SMAD4 and BMPR1A. SMAD4 mutations are \nassociated with a higher incidence of gastric polyposis. In this case report, we \ndescribe two patients with massive gastric polyposis associated with a SMAD4 \nmutation. Both presented with anaemia and both had colonic polyps. Initial \nendoscopic findings revealed giant rugal folds suggestive of Ménétrier disease. \nHowever, as other possible gastropathies could not be differentiated on the \nbasis of histology, a definitive diagnosis of JPS required additional mutation \nanalysis. In patients with polyposis predominant in or limited to the stomach, \nestablishing a diagnosis based solely on the pathological features of polyps can \nbe challenging due to difficulties in differentiating JPS from other \nhypertrophic gastropathies. Mutation analysis should be considered early in the \ndiagnostic process in cases of suspected juvenile polyposis, thus facilitating \nrapid diagnosis and adequate follow-up.",
"Juvenile polyposis syndrome (JPS) is caused by heterozygous mutations in either \nSMAD4 or BMPR1A. Individuals with JPS due to mutations in SMAD4 are at greater \nrisk to manifest signs of hereditary hemorrhagic telangiectasia (HHT). HHT is \ncaused by either mutations in SMAD4 or other genes that modulate transforming \ngrowth factor-beta (TGFβ) signaling. Additional genes in the TGFβ network \ninclude FBN1, TGFBR1, and TGFBR2, mutations of which cause either Marfan \nsyndrome (MFS) or Loeys-Dietz syndrome (LDS), respectively. As SMAD4, FBN1, and \nTGFBR1/2 map to different regions of the genome, disorders associated with \nmutations in these genes are not expected to co-segregate in a family. We report \nan individual whose family history was positive for aortopathy, mitral valve \ndysfunction, and JPS. Mutation analysis of SMAD4 implicates this gene for these \nphenotypes in this family. Although SMAD4 is among several genes in the TGFβ \nnetwork, and although prior single case reports have described large vessel \naneurysms in HHT, this is the first description of aortic and mitral disease \npresenting with JPS. This observation suggests that, in addition to HHT, \nindividuals with SMAD4 mutations may be at risk for aortic dilation and mitral \nvalve dysfunction. We emphasize the importance of comprehensive review of the \nmedical history prior to molecular testing, especially in an asymptomatic \npatient.",
"BACKGROUND: Germline mutations in SMAD4 and BMPR1A disrupt the transforming \ngrowth factor β signal transduction pathway, and are associated with juvenile \npolyposis syndrome. The effect of genotype on the pattern of disease in this \nsyndrome is unknown. This study evaluated the differential impact of SMAD4 and \nBMPR1A gene mutations on cancer risk and oncological phenotype in patients with \njuvenile polyposis syndrome.\nMETHODS: Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A \nmutations were identified from a prospectively maintained institutional \nregistry. Medical records were reviewed and the clinical patterns of disease \nwere analysed.\nRESULTS: Thirty-five patients had germline mutations in either BMPR1A (8 \npatients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was \nsimilar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 \nmutations were associated with larger polyp numbers (number of patients with 50 \nor more gastric polyps: 14 versus 0 respectively). The numbers of patients with \nrectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 \nversus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas \nfour men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal \n(1) cancer. The gastrointestinal cancer risk in patients with juvenile polyposis \nsyndrome and a SMAD4 mutation was 11 per cent (3 of 27).\nCONCLUSION: The SMAD4 genotype is associated with a more aggressive upper \ngastrointestinal malignancy risk in juvenile polyposis syndrome.",
"Author information:\n(1)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner \nResearch Institute, Cleveland Clinic, Cleveland, Ohio; Division of Medical \nOncology, National Cancer Centre, Singapore; Oncology Academic Clinical Program, \nDuke-NUS Graduate Medical School, Singapore.\n(2)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner \nResearch Institute, Cleveland Clinic, Cleveland, Ohio.\n(3)Institute of Molecular and Cell Biology, A∗STAR, Singapore.\n(4)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner \nResearch Institute, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, \nCleveland Clinic, Cleveland, Ohio.\n(5)Centre for Computational Biology, Duke-NUS Graduate Medical School, \nSingapore.\n(6)Department of Pathology, Singapore General Hospital, Singapore.\n(7)Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio; Lerner \nResearch Institute, Cleveland Clinic, Cleveland, Ohio; Taussig Cancer Institute, \nCleveland Clinic, Cleveland, Ohio; CASE Comprehensive Cancer Center, Case \nWestern Reserve University, Cleveland, Ohio; Department of Genetics and Genome \nSciences, Case Western Reserve University, Cleveland, Ohio. Electronic address: \nengc@ccf.org.",
"BACKGROUND: In patients with juvenile polyposis syndrome (JPS) the frequency of \nlarge genomic deletions in the SMAD4 and BMPR1A genes was unknown.\nMETHODS: Mutation and phenotype analysis was used in 80 unrelated patients of \nwhom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to \nhave JPS.\nRESULTS: By direct sequencing of the two genes, point mutations were identified \nin 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were \nfound in 14% of all patients with typical JPS (six deletions in SMAD4 and three \ndeletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 \nmutation negative cases uncovered a point mutation in two patients (5%). SMAD4 \nmutation carriers had a significantly higher frequency of gastric polyposis \n(73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of \ngastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation \ncarriers with gastric polyps were significantly older at gastroscopy than those \nwithout (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, \nhereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The \ndocumented histologic findings encompassed a wide distribution of different \npolyp types, comparable with that described in hereditary mixed polyposis \nsyndromes (HMPS).\nCONCLUSIONS: Screening for large deletions raised the mutation detection rate to \n60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation \nfor gastric polyposis, gastric cancer, and HHT was identified, which should have \nimplications for counselling and surveillance. Histopathological results in \nhamartomatous polyposis syndromes must be critically interpreted."
] | ['http://www.disease-ontology.org/api/metadata/DOID:0050787', 'https://meshb.nlm.nih.gov/record/ui?ui=D005796'] |
606a23c694d57fd87900004d | [
31673144,
32710457
] | train | Which two genes are predominantly considered by warfarin initial dosing algorithms? | list | Polymorphisms in CYP2C9 and VKORC1 are taken into consideration by warfarin initial dosing algorithms. | ['CYP2C9', 'VKORC1'] | [
"Author information:\n(1)Division of Clinical Pharmacology and Toxicology, The Hospital for Sick \nChildren, Toronto, ON, Canada.\n(2)Department of Pediatrics, Yokohama City University, School of Medicine, \nYokohama, Kanagawa, Japan.\n(3)Division of Clinical Research Planning, Department of Development Strategy, \nCenter for Clinical Research and Development, National Center for Child Health \nand Development, Tokyo, Japan.\n(4)Institute of Cellular Medicine, Newcastle University and Newcastle upon Tyne \nHospitals, NHS Foundation Trust, Newcastle upon Tyne, UK.\n(5)Department of Haematology, The Newcastle upon Tyne Hospitals NHS Foundation \nTrust, Newcastle upon Tyne, UK.\n(6)Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's \nHospital, Columbus, OH, US.\n(7)Division of Pediatric Hematology/Oncology, Department of Pediatrics, Monroe \nCarell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical \nCenter, Nashville, TN, US.\n(8)Assistance Publique Hôpitaux de Paris, Hôpital Necker Enfants Malades, Unité \nMédico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de \nréférence M3C, Paris, France.\n(9)University Paris Descartes, Paris, France.\n(10)Université Paris Descartes, Inserm Unité Mixte de Recherche (UMR)-S, Paris, \nFrance.\n(11)University Paris Descartes, INSERM UMR 1147, Paris, France.\n(12)Influenza and Emerging Respiratory Pathogens, BC Centre for Disease Control, \nVancouver, BC, Canada.\n(13)Division of Translational Therapeutics, Department of Pediatrics, University \nof British Columbia, Vancouver, BC, Canada.\n(14)Department of Medical Sciences, Clinical Pharmacology and Science for Life \nLaboratory, Uppsala University, Uppsala, Sweden.\n(15)Department of Pediatrics, Graduate School of Medicine and Pharmaceutical \nSciences, University of Toyama, Toyama, Japan.\n(16)Graduate School of Medicine and Pharmaceutical Sciences, University of \nToyama, Toyama, Japan.\n(17)Department of Cardiology, Kanagawa Children's Medical Center, Yokohama, \nJapan.\n(18)Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.\n(19)Department of Clinical Pharmacology & Genetics, School of Pharmaceutical \nSciences, University of Shizuoka, Shizuoka, Japan.\n(20)Division of Pediatric Hematology/Oncology, The Hospital for Sick Children, \nToronto, ON, Canada.\n(21)Division of Clinical Pharmacology and Toxicology, The Hospital for Sick \nChildren, Toronto, ON, Canada. shinya.ito@sickkids.ca.",
"WHAT IS KNOWN AND OBJECTIVE: Warfarin is an oral anticoagulant which has been \nwidely used to treat and prevent thromboembolic events. Managing warfarin \ntherapy requires careful monitoring and dose titration. This randomized \ncontrolled study was designed to assess the effect of genotype-guided warfarin \nanticoagulation in Chinese elderly patients with nonvalvular atrial \nfibrillation.\nMETHODS: 507 adults were randomized to receive initial dosing as determined by \nan algorithm containing genetic (VKORC1 and CYP2C9) plus clinical information or \nonly clinical information. The primary endpoint was the time in therapeutic \nrange (TTR) over 90 days. Secondary end points included haemorrhagic events, \nthrombotic events and mortality.\nRESULTS: The TTR was significantly different between genetic group and control \ngroup. The average TTR was (70.80 ± 24.39) % in the genotype-guided group as \ncompared with (53.44 ± 26.73) % in the control group. This represents a \ndifference of 17.36% (95% CI, 11.82 to 22.89, P < .001). The cumulative \nincidence of total haemorrhagic events, minor haemorrhagic events, \ngastrointestinal bleeding and intracerebral bleeding events was not \nsignificantly different between two groups (P > .05). Follow-up showed that the \ncumulative incidence of ischaemic stroke events occurred in the genetic group \nwas significantly lower than that in the control group (2.39% vs 6.82%), and the \ngenetic group had a significant lower risk than control group in cumulative \nincidence of ischaemic stroke events [HR 0.22, (95% CI 0.065 to 0.77), P < .05].\nWHAT IS NEW AND CONCLUSION: Genotype-guided dosing could improve the average \nTTR, and follow-up result showed that genotype-guided therapy resulted in a \nsignificantly lower risk of ischaemic stroke events. Further research is \nrequired to focus on the clinical benefit of genotype-guided dosing."
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] | train | Which two interleukins are inhibited by Ustekinumab? | list | Ustekinumab, a monoclonal antibody that binds to the shared p40 subunit of interleukin-12 and interleukin-23, is approved in the USA and Europe for moderate to severe plaque psoriasis. | ['interleukin-12', 'interleukin-23'] | [
"INTRODUCTION: Ustekinumab is a human monoclonal antibody directed against the \nshared p40 subunit of interleukins 12 and 23. Ustekinumab is currently approved \nfor the treatment of psoriatic arthritis (PsA) and moderate to severe plaque \npsoriasis, and is being evaluated in Crohn's disease (CD).\nAREAS COVERED: The first evidence supporting the efficacy of ustekinumab in the \ntreatment of moderate to severe CD was published in 2008. Results from \nsubsequent phase II and phase III randomized controlled trials (RCTs) have shown \npromising data on the clinical efficacy of induction and remission of moderate \nto severe CD. These data and the safety profile of ustekinumab will be reviewed. \nExpert commentary: As a significant proportion of individuals with CD have \nongoing symptoms and inflammation despite existing therapies, there is a \nclinical need for new agents like ustekinumab directed at different targets on \nthe inflammatory pathway. Looking forward, more studies are needed to evaluate \ndosing escalation or de-escalation in addition to timing of therapy switches. In \naddition, further data is required to gauge the comparative effectiveness of \nustekinumab to the biologic agents that are currently used in the treatment of \nCD.",
"Pyoderma gangrenosum (PG) is an orphan disease. While research on such disorders \nis based on only few randomized multicenter as well as retrospective studies, \nmost of the data comes from case series of small patient groups. Apart from \ntopical and intralesional therapeutic options for early stages and mild disease \ncourses, treatment predominantly involves systemic therapeutic agents. Besides \nsystemic corticosteroids and cyclosporine A (CsA), options also include \nintravenous immunoglobulins (IVIG) and biologics such as the TNFα inhibitors \ninfliximab, adalimumab, and etanercept; the interleukin (IL) 12/23 antibody \nustekinumab; the IL-1 receptor antagonist anakinra; and the IL-1β antibody \ncanakinumab. The best evidence-based study data is available for CsA, \nprednisolone, and infliximab; the latter especially in patients with concomitant \nulcerative colitis or Crohn's disease. A response to IVIG and canakinumab has \nbeen reported in smaller case series. First described by Brocq almost 100 years \nago, it was soon recognized that PG did in fact require treatment. To this day, \nhowever, such treatment remains a clinical challenge. Despite the severe - \nalbeit rare -clinical picture, improvement in therapeutic options may be \nexpected in the future, primarily due to further clinical studies - especially \nwith a greater number of patients, a better understanding of the \netiopathogenesis, as well as the use of modern targeted therapies with higher \nefficacy and a lower rate of side effects than conventional immunosuppressants \nsuch as prednisolone and CsA.",
"BACKGROUND: Interleukin-23 is thought to be critical to the pathogenesis of \npsoriasis. We compared risankizumab (BI 655066), a humanized IgG1 monoclonal \nantibody that inhibits interleukin-23 by specifically targeting the p19 subunit \nand thus prevents interleukin-23 signaling, and ustekinumab, an interleukin-12 \nand interleukin-23 inhibitor, in patients with moderate-to-severe plaque \npsoriasis.\nMETHODS: We randomly assigned a total of 166 patients to receive subcutaneous \ninjections of risankizumab (a single 18-mg dose at week 0 or 90-mg or 180-mg \ndoses at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body \nweight, at weeks 0, 4, and 16). The primary end point was a 90% or greater \nreduction from baseline in the Psoriasis Area and Severity Index (PASI) score at \nweek 12.\nRESULTS: At week 12, the percentage of patients with a 90% or greater reduction \nin the PASI score was 77% (64 of 83 patients) for risankizumab (90-mg and 180-mg \ngroups, pooled), as compared with 40% (16 of 40 patients) for ustekinumab \n(P<0.001); the percentage of patients with a 100% reduction in the PASI score \nwas 45% in the pooled 90-mg and 180-mg risankizumab groups, as compared with 18% \nin the ustekinumab group. Efficacy was generally maintained up to 20 weeks after \nthe final dose of 90 or 180 mg of risankizumab. In the 18-mg and 90-mg \nrisankizumab groups and the ustekinumab group, 5 patients (12%), 6 patients \n(15%), and 3 patients (8%), respectively, had serious adverse events, including \ntwo basal-cell carcinomas and one major cardiovascular adverse event; there were \nno serious adverse events in the 180-mg risankizumab group.\nCONCLUSIONS: In this phase 2 trial, selective blockade of interleukin-23 with \nrisankizumab was associated with clinical responses superior to those associated \nwith ustekinumab. This trial was not large enough or of long enough duration to \ndraw conclusions about safety. (Funded by Boehringer Ingelheim; \nClinicalTrials.gov number, NCT02054481 ).",
"BACKGROUND: Ustekinumab, an interleukin-12/23 inhibitor, is effective in the \ntreatment of psoriasis. A recent Italian study showed more favourable response \nto ustekinumab in patients with positive human leucocyte antigen (HLA)-Cw6. \nNonetheless, there are differences in genetic susceptibility to psoriasis \nbetween races, and no studies have specifically assessed the candidate genetic \nmarkers in predicting therapy outcome in Chinese patients with psoriasis treated \nwith ustekinumab.\nOBJECTIVES: To determine whether HLA gene polymorphisms can predict the response \nto ustekinumab in Chinese patients with psoriasis.\nMETHODS: Sixty-six patients with psoriasis treated with ustekinumab were \nincluded in the study, and the effectiveness of ustekinumab therapy was \nevaluated at weeks 0, 16 and 28 by Psoriasis Area and Severity Index (PASI).\nRESULTS: More HLA-Cw6-positive patients achieved a PASI 75 response at week 4 \ncompared with HLA-Cw6-negative patients (38% vs. 9%, P = 0·019). Similarly, at \nweek 16, patients carrying the HLA-Cw6 allele showed a higher likelihood of \nachieving PASI 50, 75 and 90 than Cw6-negative patients, although this was not \nstatistically significant. At week 28, a significantly higher percentage of \nHLA-Cw6-positive patients maintained PASI 90 response compared with Cw6-negative \npatients (63% vs. 26%, P = 0·035). Further analysis of other HLA allele \npolymorphisms did not show significant associations with therapeutic response to \nustekinumab.\nCONCLUSIONS: This pharmacogenetic study provides preliminary data indicating \nthat positive HLA-Cw6 is associated with a good response to ustekinumab \ntreatment in Chinese patients with psoriasis.",
"BACKGROUND: Biologic agents offer a range of new therapeutic options for \npatients with psoriasis; however, the relative benefit-risk profiles of such \ntherapies are not well known. We compared two biologic agents, ustekinumab (an \ninterleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor \nnecrosis factor alpha), for the treatment of psoriasis.\nMETHODS: We randomly assigned 903 patients with moderate-to-severe psoriasis to \nreceive subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 \nand 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). The primary \nend point was the proportion of patients with at least 75% improvement in the \npsoriasis area-and-severity index (PASI) at week 12; a secondary end point was \nthe proportion with cleared or minimal disease on the basis of the physician's \nglobal assessment. Assessors were unaware of the treatment assignments. The \nefficacy and safety of a crossover from etanercept to ustekinumab were evaluated \nafter week 12.\nRESULTS: There was at least 75% improvement in the PASI at week 12 in 67.5% of \npatients who received 45 mg of ustekinumab and 73.8% of patients who received 90 \nmg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, \nrespectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab \nand 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal \ndisease according to the physician's global assessment, as compared with 49.0% \nof those who received etanercept (P<0.001 for both comparisons). Among patients \nwho did not have a response to etanercept, 48.9% had at least 75% improvement in \nthe PASI within 12 weeks after crossover to ustekinumab. One or more adverse \nevents occurred through week 12 in 66.0% of patients who received 45 mg of \nustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% \nwho received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse \nevents. Safety patterns were similar before and after crossover from etanercept \nto ustekinumab.\nCONCLUSIONS: The efficacy of ustekinumab at a dose of 45 or 90 mg was superior \nto that of high-dose etanercept over a 12-week period in patients with \npsoriasis. (ClinicalTrials.gov number, NCT00454584.)",
"The pathogenesis of psoriasis is unknown, although it is generally accepted that \nthis chronic inflammatory skin disorder is a complex autoimmune condition \nsimilar to other T-cell mediated disorders. Psoriasis imposes a heavy burden on \nthe lifestyle of those affected due to the psychological, arthritic, and \ncutaneous morbidities; thus significant research has focused on the genetic and \nimmunologic features of psoriasis in anticipation of more targeted, efficacious, \nand safe therapies. Recently, CD4(+) T helper (Th) 17 cells and interleukins \n(IL)-12 and -23 have been important in the pathogenesis of T-cell mediated \ndisorders such as psoriasis and has influenced the development of medications \nthat specifically target these key immunological players. Ustekinumab is a \nmonoclonal antibody belonging to a newly developed class of biological, \nanti-cytokine medications that notably targets the p40 subunit of both IL-12 and \n-23, both naturally occurring proteins that are important in regulating the \nimmune system and are understood to play a role in immune-mediated inflammatory \ndisorders. Ustekinumab's safety and efficacy has been evaluated for the \ntreatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, \n2 placebo-controlled (PHOENIX 1 and 2), and 1 comparator-controlled (ACCEPT) \nstudy which proved advantageous in patients who were treatment-naive, previously \nfailed other immunosuppressive medications including cyclosporine or \nmethotrexate, were unresponsive to phototherapy, or were unable to use or \ntolerate other therapies. Ustekinumab has also been investigated for other \nindications such as psoriatic arthritis, Crohn's disease, and \nrelapsing/remitting multiple sclerosis. We present a concise review evaluating \nthe evidence that supports the use of ustekinumab in the treatment of plaque \npsoriasis and other conditions.",
"BACKGROUND: Ustekinumab, a fully human immunoglobulin (Ig) G1K monoclonal \nantibody directed against the p40 subunit of interleukin (IL)-12/23, has \ndemonstrated efficacy in patients with moderate-to-severe psoriasis.\nOBJECTIVE: To evaluate the effect of IL-12/23 inhibition on immunocompetency by \nantigen-recall response in a preclinical multiple-dose toxicology study and \nthree single-dose, phase 1 studies.\nMETHODS: Cynomolgus monkeys (Mauritius; n = 32) treated with subcutaneous (s.c.) \nplacebo or ustekinumab 22.5 or 45 mg/kg twice weekly for 26 weeks were assessed \nfor antibody responsiveness to keyhole limpet hemocyanin (KLH). Patients with \npsoriasis or multiple sclerosis who received a single-dose of placebo (n = 8) or \nustekinumab (n = 46) 0.09-4.5 mg/kg intravenous (i.v.) or 0.27-2.7 mg/kg s.c. \nwere assessed by pneumococcal and tetanus antigen challenge. Primary T-cell \nresponse was not assessed in humans.\nRESULTS: Anti-KLH antibody responses in ustekinumab-treated cynomolgus monkeys \nwere comparable to those observed in placebo-treated animals. A normal antibody \nresponse (> or = two-fold increase from baseline) to pneumococcal antigen was \nseen in 34/46 (73.9%) ustekinumab-treated versus 4/8 (50%) placebo-treated \npatients. A normal antigen-recall response (> or = four-fold increase from \nbaseline) was seen in 12/20 (60%) ustekinumab- and 4/5 (80%) placebo-treated \npatients following tetanus toxoid exposure. Percentages of circulating immune \ncells were not affected by ustekinumab treatment.\nCONCLUSION: Results in nonhuman primates and human patients suggest that \nustekinumab treatment does not significantly impair recall humoral immune system \nfunctions.",
"BACKGROUND: Repeated subcutaneous injections of a monoclonal antibody against \nthe p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat \npatients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug's \nsafety, efficacy, and pharmacokinetics.\nMETHODS: In this phase II, multicentre, randomised, double-blind, \nplacebo-controlled study, 249 patients with RRMS, aged 18-65 years, were \neligible to be assigned equally (by a central randomisation procedure based on \nstudy site and presence or absence of gadolinium-enhancing T1-weighted lesions \nat baseline) to one of five groups that received placebo or four different \nustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses \nwere 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received \nplacebo substitute at weeks 7 and 15. The primary endpoint was the cumulative \nnumber of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI \nthrough week 23. Patients were followed up through week 37. Analysis was by \nintention to treat. This trial is registered with ClinicalTrials.gov, number \nNCT00207727.\nFINDINGS: From August, 2004, to December, 2006, 249 patients underwent \nrandomisation (49 for placebo; 50 for each ustekinumab group). Ustekinumab \ntreatment did not show a significant reduction in the primary endpoint for any \ndosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) \nplacebo-treated patients and 170 (85%) ustekinumab-treated patients, with \ninfections most commonly reported. Serious adverse events occurred in one (2%) \nplacebo-treated patient and six (3%) ustekinumab-treated patients. Malignant \ndiseases were reported in two patients shortly after the initiation of \nustekinumab treatment; both patients were withdrawn from the trial and given \nappropriate treatment, which resulted in complete remission. No serious \ninfections, cardiovascular events, or exacerbation of demyelinating events \noccurred. A dose-dependent increase in serum concentrations of ustekinumab was \nrecorded.\nINTERPRETATION: Ustekinumab is generally well tolerated but does not show \nefficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted \nlesions in multiple sclerosis.",
"(1) For adults with plaque psoriasis, after failure of topical symptomatic \ntreatments and PUVA therapy, several systemic immunosuppressive agents are \nacceptable for severe disease: methotrexate, then ciclosporin, and possible a \nTNF alpha antagonist (etanercept, etc.); (2) Ustekinumab is an inhibitor of \ninterleukins 12 and 23, which are believed to be implicated in the onset of \npsoriasis. It is authorized in the European Union for patients who fail to \nrespond to conventional systemic treatments; (3) In one trial with a low level \nof evidence (single-blind), 2 subcutaneous injections of ustekinumab at an \ninterval of 4 weeks appeared to be statistically more effective than \ntwice-weekly subcutaneous injections of etanercept for 12 weeks. More patients \nachieved a 75% reduction in the score most widely used to evaluate the extent \nand intensity of plaque psoriasis lesions (PASI score): about 71% versus 57%. \nThe results beyond this period have not been reported; (4) Two randomised, \ndouble-blind, placebo-controlled trials in a total of 1996 patients showed that \nat least two-thirds of patients treated with ustekinumab achieved at least a 75% \nreduction in their PASI score versus fewer than 4% with placebo; (5) In animal \nstudies, interleukin 12 and 23 inhibitors cause cancer. There is therefore a \nhigh risk of cancer developing during prolonged treatment with ustekinumab; (6) \nThe main adverse effects identified in clinical trials include infections, \ninjection-site reactions, psychological disorders and development of \nanti-ustekinumab antibodies; (7) There is insufficient follow-up to evaluate the \ncardiac risks associated with ustekinumab; (8) As maintenance therapy, \nustekinumab is administered as one subcutaneous injection every 12 weeks. This \npractical advantage compared to TNF alpha antagonists must be weighed against \nthe risks inherent in prolonged immunosuppression; (9) In summary, for \nsymptomatic relief of patients whose psoriasis poses major problems despite \ntreatment with methotrexate or ciclosporin, in the absence of a better \nalternative, it is better to use a TNF alpha antagonist and to avoid exposing \npatients to the risks associated with ustekinumab, particularly its carcinogenic \nrisk.",
"Only limited data on laboratory parameter dynamics and safety under prolonged \nbiologic treatment in a \"real-world\" scenario are available for recommendations \non screening and monitoring. This study is a retrospective analysis of routine \nparameter dynamics and laboratory adverse events (LAE) in psoriasis patients on \nlong-term treatment (n = 199) with tumour necrosis factor (TNF)-α-antagonists \n(adalimumab, etanercept), and the interleukin (IL)12/23-antagonist ustekinumab. \nOverall, neutrophil (PMN) counts (-11%) and triglycerides (+9%) changed \nconsiderably. TNF-α-antagonists and ustekinumab differentially affected \nlymphocyte counts (+13% and ±0%, respectively). Dynamics were pronounced during \nthe first 180 days of treatment. In 340 treatment-years, 15 Common Terminology \nCriteria for Adverse Events (CTCAE) III-IV° LAE were recorded (11 involved liver \nenzymes). They prompted alteration of the biologic regime in only 2 cases. Age, \nsex, previous systemic treatments, and psoriatic arthritis did not significantly \npredict LAE. Liver enzyme and triglyceride screening may be warranted in some \ninstances. Our data suggest that unguided monitoring of other routine laboratory \nparameters is unnecessary under long-term biologic treatment.",
"Ustekinumab is a fully human monoclonal antibody directed against the p40 \nsubunit shared by interleukin 12 and interleukin 23, two naturally occurring \nprotein regulators that play an important role in immune-mediated inflammatory \ndiseases, including psoriatic arthritis (PsA). In September of 2009, the US FDA \napproved ustekinumab for the treatment of adult patients with moderate to severe \nplaque psoriasis. Beginning in November of 2009, Janssen Biotech (formerly \nCentocor Biotech), the developer of ustekinumab, initiated clinical trials to \ninvestigate the efficacy of ustekinumab in the treatment of other inflammatory \ndisorders, including PsA. Phase II and Phase III studies showed both a good \nsafety profile and significant efficacy for ustekinumab in the treatment of PsA, \nleading to the drug's approval in both Europe and the USA. In an immunotherapy \nmarket currently dominated by anti-TNF-α drugs for the treatment of PsA, \nustekinumab offers an alternative option for patients with PsA, including those \nunresponsive to methotrexate and the TNF-α inhibitory agents currently approved \nfor this potentially debilitating disease.",
"Psoriasis is a complex systemic immune inflammatory disease whose burden of \ndisease includes poorer quality of life, a high prevalence of serious \ncomorbidities, and a potentially decreased life span-hence the continued need to \nsearch for new treatment options. ABT-874 (Abbott Laboratories, Saint-Laurent, \nQC,) and ustekinumab (CNTO 1275, Ortho Biotech, Toronto, ON) are two monoclonal \nantibodies against interleukins 12 and 23 (IL-12/23), key mediators of T-cell \ndifferentiation in the pathogenesis of psoriasis. The results of a 12-week, \nphase II, dose-finding study of ABT-874 have been encouraging. More recently, \nlevel 1 evidence has emerged for ustekinumab in two placebo-controlled phase III \ntrials, PHOENIX 1 and PHOENIX 2; therapeutic responses to ustekinumab have been \nmaintained up to 76 weeks of follow-up, and quality of life has significantly \nimproved with ustekinumab. Both agents produced few and mild adverse events, and \nthe rates of serious infections and cancers were very low and similar to those \nof placebo. These promising results strongly confirm the central role of \nIL-12/23 in psoriasis and its importance as a therapeutic target.",
"Psoriasis is a chronic, genetically determined, immune-mediated, inflammatory \nskin disease affecting approximately 2% to 3% of Caucasian population. Given the \nwell-established role of the immuno-mediated inflammation in the pathogenesis of \npsoriasis, in the past few years several key steps in the pathogenesis of this \ndisease have been elucidated and the increased knowledge led to the development \nof specific drugs, commonly defined as \"biologics\" targeting one or more of \nthese steps. At present an anti-CD11a antibody (efalizumab), an anti-LFA3/CD2 \nreceptor (alefacept) and 3 antitumor necrosis factor alpha agents (adalimumab, \netanercept, infliximab) are now commercially available for the treatment of both \npsoriasis and psoriatic arthritis. Recent studies have demonstrated that \ninterleukins (IL) 12 and 23 play an important role in the pathophysiology of \npsoriasis. In fact members of the IL-12 family of cytokines have the potential \nto act as the next major cytokine(s) in pathogenesis and the treatment of \npsoriasis. Ustekinumab (CNTO 1275, Centocor Inc, Malvern, PA, USA) is a human \nmonoclonal antibody that binds to the shared p40 protein subunit of human \ninterleukins 12 and 23 with high affinity and specificity, thereby preventing \ninteraction with their surface IL-12Rβ1 receptor. Different clinical studies \nhave been conducted to date. In particular a phase II study and two phase III \nstudies, PHOENIX 1 together with PHOENIX 2, show very encouraging results. This \nreview reports on the latest progress made in the clinical use of biologic drugs \nfor psoriasis focusing on the new human IL-12/23 monoclonal antibody, \nustekinumab, for psoriasis.",
"INTRODUCTION: The biologic, Ustekinumab (Stelara®, Centocor, Inc., Malvern, PA, \nUSA), is a fully human monoclonal antibody with a high affinity for the shared \np40 subunit of interleukins 12 and 23 (IL-12 and IL-23). Approved for use in \ntreating moderate-to-severe psoriasis in 2009, there has been considerable \ninterest in the long-term safety of ustekinumab.\nAREAS COVERED: This review discusses the use of ustekinumab in the treatment of \npsoriasis and its potential to be an effective and well-tolerated therapy. A \nliterature search was performed for articles published through April 2013 to \nidentify any safety concerns.\nEXPERT OPINION: Our results indicate that ustekinumab has demonstrated higher \nefficacy rates as compared to traditional therapies; and with a favorable dosing \nschedule and stable safety profile, patients with recalcitrant disease will now \nhave another option for treatment.",
"Ustekinumab is a monoclonal antibody directed against the p40 subunit, which is \npart of interleukins IL-12 and IL-23. The efficacy of ustekinumab versus placebo \nin terms of clinical response and remission of induction has been shown in \nphase3 clinical trials. When used as subcutaneous maintenance therapy, the \ntherapeutic benefit of ustekinumab over placebo has been confirmed in both \nclinical response and remission in patients who have responded clinically to \ninduction therapy. In addition, ustekinumab has demonstrated an improvement in \nmucosal healing parameters. The safety profile of the drug has been good, with \nlow infection rates (without reactivation of tuberculosis) and absence of tumour \nreporting. The development of drug immunogenicity appears to be rare. In \nsummary, ustekinumab is a promising treatment option in patients with Crohn's \ndisease, as an alternative to anti-TNFα drugs.",
"Recent advances in the therapeutics of psoriatic arthritis (PsA) have provided \nmore options to clinicians managing PsA. The purpose of this review is to update \nthe reader on treatment options for PsA using conventional synthetic disease \nmodifying agents (csDMARDs) and novel therapies including tumour necrosis factor \nalpha inhibitors, interleukin 12/23 inhibitor (ustekinumab), the interleukin 17 \nantagonists including secukinumab, brodalumab, ixekizumab, and the \nphosphodiesterase-4 inhibitor, apremilast. Areas covered: We reviewed published \narticles on the treatment of PsA. Our main sources of data included treatment \nrecommendations, registry studies, systematic literature reviews, major \nrandomised controlled trials for more recently approved drugs, and abstracts \nfrom the American College of Rheumatology and EULAR meetings. Expert commentary: \nAn overview of the evidence for the use of various pharmacotherapeutic agents \nfor treatment of this heterogeneous disease was compiled. Treatment options for \nthe various domains of PsA are also discussed.",
"OBJECTIVE: Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, \neffects on radiographic progression in psoriatic arthritis (PsA).\nMETHODS: We conducted preplanned integrated analyses of combined radiographic \ndata from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. \nPatients had active PsA despite prior conventional and/or biologic \ndisease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, \nC-reactive protein ≥3.0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, \nn=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or \nplacebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with <5% \nimprovement in tender/swollen joint counts entered blinded early escape. All \nother placebo patients received ustekinumab 45 mg at wk 24 and wk 28, then q 12 \nwks. Radiographs of hands/feet at wks 0/24/52 were assessed using PsA-modified \nvan der Heijde-Sharp (vdH-S) scores; combined PSUMMIT-1 and PSUMMIT-2 changes in \ntotal vdH-S scores from wk 0 to wk 24 comprised the prespecified primary \nradiographic analysis. Treatment effects were assessed using analysis of \nvariance on van der Waerden normal scores (factors=treatment, baseline \nmethotrexate usage, and study).\nRESULTS: Integrated data analysis results indicated that ustekinumab-treated \npatients (regardless of dose) demonstrated significantly less radiographic \nprogression at wk 24 than did placebo recipients (wk 0-24 total vdH-S score mean \nchanges: 0.4-combined/individual ustekinumab dose groups, 1.0-placebo; all \np<0.02). From wk 24 to wk 52, inhibition of radiographic progression was \nmaintained for ustekinumab-treated patients, and progression was substantially \nreduced among initial placebo recipients who started ustekinumab at wk 16 or wk \n24 (wk 24 - wk 52, total vdH-S score mean change: 0.08).\nCONCLUSIONS: Ustekinumab 45 and 90 mg treatments significantly inhibited \nradiographic progression of joint damage in patients with active PsA.",
"Monoclonal antibody (mAb) therapy was first established upon the approval of a \nmouse antibody for treatment of human acute organ rejection. However, the high \nincidence of immune response against the mouse mAb restricted therapeutic \nutility. Development of chimeric, \"humanized\" and human mAbs broadened \ntherapeutic application to immune-mediated diseases requiring long-term \ntreatment. Indeed, mAb therapeutics targeting soluble cytokines are highly \neffective in numerous immune-mediated disorders. A recent example is \nustekinumab, a first-in-class therapeutic human immunoglobulin G1 kappa mAb that \nbinds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte \nfunction, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was \ngenerated via recombinant human IL-12 immunization of human immunoglobulin \n(hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 \nand IL-23 and prevents their interaction with the IL-12 receptor β1 subunit of \nthe IL-12 and IL-23 receptor complexes. Ustekinumab is approved for treatment of \nmoderate-to-severe plaque psoriasis and has demonstrated efficacy in Crohn \ndisease and psoriatic arthritis. The clinical characterization of ustekinumab \ncontinues to clarify our understanding of human immune pathologies and may offer \na novel therapeutic option for certain immune-mediated diseases.",
"BACKGROUND: Ustekinumab is a human monoclonal antibody that binds to the p40 \nsubunit of interleukin (IL) 12 and IL-23 and inhibits their pharmacological \nactivity. To evaluate potential effects of ustekinumab treatment during \npregnancy, developmental studies were conducted in cynomolgus macaques.\nMETHODS: Ustekinumab was tested in two embryo/fetal development (EFD) studies \nand in a combined EFD/pre and postnatal development (PPND) study. In the EFD \nstudies, pregnant macaques (12/group) were dosed with saline or ustekinumab (9 \nmg/kg IV, 22.5 mg/kg SC, or 45 mg/kg IV or SC during the period of major \norganogenesis, gestation day [GD] 20-50). Fetuses were harvested on GD100-102 \nand examined for any effects on development. In the EFD/PPND study, pregnant \nmacaques were injected with saline or ustekinumab (22.5 or 45 mg/kg SC) from \nGD20 through lactation day 33. Infants were examined from birth through 6 months \nof age for morphological and functional development. Potential effects on the \nimmune system were evaluated by immunophenotyping of peripheral blood \nlymphocytes and immunohistopathology of lymphoid tissues in fetuses and infants \nand by T-dependent antibody response (TDAR) to KLH and TTX and by DTH response \nin infants. Ustekinumab concentrations were measured in serum from dams, fetus, \nand infants and in breast milk.\nRESULTS: Ustekinumab treatment produced no maternal toxicity and no toxicity in \nthe fetuses or infants, including no effects on the TDAR or DTH responses. \nUstekinumab was present in serum from GD100 fetuses and was present in infant \nserum through day 120 post-birth. Low levels of ustekinumab were present in \nbreast milk.\nCONCLUSIONS: Exposure of macaque fetuses and infants to ustekinumab had no \nadverse effects on pre- and postnatal development.",
"Ustekinumab, a monoclonal antibody that binds to the shared p40 subunit of \ninterleukin (IL)-12 and IL-23, is approved in the USA and Europe for moderate to \nsevere plaque psoriasis. There are concerns that biologic treatments like \nustekinumab may lead to an increased rate of infections. We report a 77-year-old \nwoman who developed varicella zoster virus meningitis 8 weeks after initiation \nof ustekinumab therapy because of plaque psoriasis. She presented clinically \nwith sudden onset of fatigue, vertigo, nausea and epileptic seizures. \nInvestigations of the cerebrospinal fluid revealed 522/3 cells, lactate \n2.9 mmol/L, protein 232 mg/dL and 2.4 × 103 varicella zoster virus. After \n3 weeks of therapy with acyclovir she recovered. We conclude that infection by \nvaricella zoster virus has to be considered as a differential diagnosis in \npatients with newly developing neurological or psychiatric abnormalities under \nimmunosuppressive therapy.",
"The use of monoclonal antibodies against interleukin (IL)-12 and -23, such as \nustekinumab, has considerably reduced the disease burden in many patients with \nmoderate to severe psoriasis. Reversible posterior leukoencephalopathy syndrome \n(RPLS) is a neurologic disorder that has been documented with increased \nfrequency with the use of systemic and biologic agents. We report a case of a \n58-year-old man with psoriasis who presented with confusion and memory \ndifficulties after being on treatment with ustekinumab for over six years. \nImaging with CT and MRI revealed mild parenchymal edema with the typical \nappearance and distribution of RPLS, confirming the diagnosis of this condition. \nThis case reports the second case of RPLS associated with ustekinumab treatment, \nwith the only other known case reported during clinical trials. With the \nincreasing use of biologics in patients with moderate to severe psoriasis, it is \ncritical that clinicians are cognizant of this potential associated adverse \nevent. <p><em>J Drugs Dermatol. 2017;16(2):177-179.</em></p>.",
"Psoriatic arthritis (PsA) is a chronic inflammatory seronegative \nspondyloarthritis associated with psoriasis. While TNF-α inhibitors have \nrevolutionized the treatment of rheumatic diseases, including PsA, not all \npatients respond to these agents while others are unsuitable or intolerant to \nthem. Thus, there is a need for additional treatment modalities with a novel \nmechanism of action. In the past years, the IL-23/Th17 axis has emerged as an \nimportant mechanism in the pathogenesis of PsA. Ustekinumab, a fully human IgG1κ \nmonoclonal antibody that targets the common subunit p40 of IL-12 and IL-23, has \nbeen shown in clinical trials, to be well-tolerated and effective in patients \nwith active PsA. It improved signs and symptoms of PsA, inhibited radiographic \nprogression and was effective in dactylitis, enthesitis, and skin disease, with \na safety profile consistent with the one observed in patients with psoriasis. \nMoreover, it was to be effective in anti-TNF-α experienced patients, definitely \nfulfilling an unmet need in the management of PsA.",
"Ustekinumab is a fully human monoclonal antibody that binds with high \nspecificity and affinity to the cytokines interleukin (IL)-12 and IL-23, thereby \nsuppressing IL-12- and IL-23-mediated inflammation associated with psoriasis. In \ntwo large, phase III trials in patients with moderate to severe plaque \npsoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients \n(administered as two injections 4 weeks apart) than placebo recipients achieved \na 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 \nweeks. Other efficacy measures, including the physician's global assessment of \nclinical response at week 12, also favored ustekinumab over placebo. Psoriatic \nsymptom control was maintained during ustekinumab maintenance therapy \n(administered once every 12 weeks) for up to 76 weeks. In a phase II trial in \npatients with active plaque psoriasis and psoriatic arthritis, signs and \nsymptoms of arthritis and psoriatic symptom control were improved to a greater \nextent with ustekinumab than with placebo at 12 weeks, based on the proportion \nof patients achieving a 20% improvement in American College of Rheumatology \nresponse criteria (arthritis) or PASI 75 (skin symptoms). Health-related quality \nof life, assessed using the Dermatology Life Quality Index and the Health \nAssessment Questionnaire disability index, was improved to a significantly \ngreater extent with ustekinumab than with placebo at week 12. Subcutaneous \nustekinumab was generally well tolerated in clinical trials, with most \ntreatment-emergent adverse events being of mild severity.",
"Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two \ncytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal \nrole in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic \nmonoclonal antibody (mAb) targeted against the p40 shared subunit of IL-12 and \nIL-23. Recently the ability of therapeutic proteins (TP) including mAbs that \ntarget either cytokines directly (e.g., Pegasys; peginterferon α-2a) or their \nrespective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to \ndesuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been \ndemonstrated. In the present study the ability of IL-12 and IL-23 to suppress \nmultiple P450 enzymes was investigated in vitro using six separate lots of \ncultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for \n48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 \ngene expression or functional activity was observed. None of the untreated \nhepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. \nSimilar results were seen with whole human liver samples. Exposure of \nhepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor \nnecrosis factor-α) or known P450 inducers (β-naphthoflavone, phenobarbital, and \nrifampicin) did not appreciably alter the expression of the IL-12 and IL-23 \nreceptors either. Finally, in contrast to the positive control IL-6, expression \nof the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 \ntreatment. Together, these data suggest a negligible propensity for IL-12 or \nIL-23 to directly alter P450 enzymes in human hepatocytes.",
"Ustekinumab, a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that \nbinds with high affinity to human interleukin-12 and interleukin-23, has \ndemonstrated efficacy in patients with psoriasis. The objective of this study \nwas to perform exposure-response modeling to increase the understanding of \nreduction in disease severity following treatment with ustekinumab in patients \nwith moderate to severe psoriasis who participate in two phase III studies \n(PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive \nustekinumab 45 mg or 90 mg (n = 1312; 11,624 Psoriasis Area and Severity Index \n[PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was \nassessed using PASI scores. A population mechanism-based exposure-response model \nof ustekinumab using NONMEM was developed using serum ustekinumab concentrations \nand PASI scores. The pharmacodynamic response effect was the reduction in PASI \nscore. The placebo effect, although minor, was also integrated into the model. \nNone of the covariate factors evaluated (eg, demographics, baseline disease \ncharacteristics, comorbidities) significantly contributed to the between-subject \nvariability in the pharmacodynamic parameters. The developed exposure-response \nmodel can serve as a basis to support future alternative dosing regimens for \nustekinumab in patients with moderate to severe plaque psoriasis. A robust \nexposure-response relationship has been confirmed for ustekinumab in psoriasis.",
"Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease with a \nbroad clinical spectrum and variable course. It can involve musculoskeletal \nstructures as well as skin, nails, eyes, and gut. The management of PsA has \nchanged tremendously in the last decade, thanks to an earlier diagnosis, an \nadvancement in pharmacological therapies, and a wider application of a \nmultidisciplinary approach. The commercialization of tumor necrosis factor \ninhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, and \ninfliximab) as well as interleukin (IL)-12/23 (ustekinumab) and IL-17 \n(secukinumab) inhibitors is representative of a revolution in the treatment of \nPsA. No evidence-based strategies are currently available for guiding the \nrheumatologist to prescribe biological drugs. Several international and national \nrecommendation sets are currently available with the aim to help rheumatologists \nin everyday clinical practice management of PsA patients treated with biological \ntherapy. Since no specific biological agent has been demonstrated to be more \neffective than others, the drug choice should be made according to the available \nsafety data, the presence of extra-articular manifestations, the patient's \npreferences (e.g., administration route), and the drug price. However, future \nstudies directly comparing different biological drugs and assessing the efficacy \nof treatment strategies specific for PsA are urgently needed.",
"OBJECTIVE: Interleukin (IL)-12 and IL-23 have been implicated in the \npathogenesis of rheumatoid arthritis (RA). The safety and efficacy of \nustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a \nhuman monoclonal anti-IL-23 antibody, were evaluated in adults with active RA \ndespite methotrexate (MTX) therapy.\nMETHODS: Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks \n0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks \n(n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab \n50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 \nand every 8 weeks (n=54) through week 28; all patients continued a stable dose \nof MTX (10-25 mg/week). The primary end point was the proportion of patients \nwith at least a 20% improvement in the American College of Rheumatology criteria \n(ACR 20) at week 28. Safety was monitored through week 48.\nRESULTS: At week 28, there were no statistically significant differences in the \nproportions of patients achieving an ACR 20 response between the combined \nustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with \nplacebo (40.0%) (p=0.101 and p=0.877, respectively). Through week 48, the \nproportions of patients with at least one adverse event (AE) were comparable \namong the treatment groups. Infections were the most common type of AE.\nCONCLUSIONS: Treatment with ustekinumab or guselkumab did not significantly \nreduce the signs and symptoms of RA. No new safety findings were observed with \neither treatment.\nTRIAL REGISTRATION NUMBER: NCT01645280.",
"BACKGROUND: Interleukins 12 and 23 have important roles in the pathophysiology \nof psoriasis. We assessed ustekinumab, a human monoclonal antibody directed \nagainst these cytokines, for the treatment of psoriasis.\nMETHODS: In this phase III, parallel, double-blind, placebo-controlled study, \n766 patients with moderate-to-severe psoriasis were randomly assigned to receive \nustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 \nweeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to \nustekinumab at week 12. Patients who were initially randomised to receive \nustekinumab at week 0 who achieved long-term response (at least 75% improvement \nin psoriasis area and severity index [PASI 75] at weeks 28 and 40) were \nre-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment \nuntil loss of response. Both randomisations were done with a minimisation method \nvia a centralised interactive voice response system. The primary endpoint was \nthe proportion of patients achieving PASI 75 at week 12. Analyses were by \nintention to treat. This study is registered with ClinicalTrials.gov, number \nNCT00267969.\nFINDINGS: All randomised patients were included in the efficacy analysis. 171 \n(67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab \n90 mg, and eight (3.1%) receiving placebo achieved PASI 75 at week 12 \n(difference in response rate vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 \nmg and 63.3%, 57.1-69.4, p<0.0001 for 90 mg). At week 40, long-term response had \nbeen achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg \ngroup. Of these, 162 patients were randomly assigned to maintenance ustekinumab \nand 160 to withdrawal. PASI 75 response was better maintained to at least 1 year \nin those receiving maintenance ustekinumab than in those withdrawn from \ntreatment at week 40 (p<0.0001 by log-rank test). During the placebo-controlled \nphase, adverse events occurred in 278 (54.5%) of the 510 patients receiving \nustekinumab and 123 (48.2%) of the 255 receiving placebo. Serious adverse events \noccurred in six (1.2%) of 510 patients receiving ustekinumab and in two (0.8%) \nof 255 receiving placebo in this phase. The pattern of adverse events was much \nthe same in the placebo crossover and randomised withdrawal phases as it was in \nthe placebo-controlled phase.\nINTERPRETATION: Ustekinumab seems to be efficacious for the treatment of \nmoderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at \nleast a year in most patients.",
"IMPORTANCE: Treatment of pityriasis rubra pilaris (PRP) is solely based on its \nresemblance to psoriasis rather than any knowledge of its pathomechanism. \nInsight into pathogenic mediators of inflammation is essential for targeted and \nvalid treatment options that could replace previous serendipitous therapeutic \napproaches in refractory PRP.\nOBJECTIVE: To determine whether blockade of the interleukin 23-helper T cell 17 \n(IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on \nits proinflammatory cytokine profile, targeted treatment option in PRP.\nDESIGN, SETTING, AND PARTICIPANTS: In this case report, a patient with PRP \nreceived outpatient treatment at a university hospital department of dermatology \nwith ustekinumab according to the dosing regimen approved for psoriasis. \nLesional skin biopsy samples were taken from this patient and 2 others with \nrefractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and \nT-cell-derived cytokines were measured and compared with skin samples from \npatients with psoriasis and healthy donors. From 1 patient, lesional skin \nsamples were taken before ustekinumab treatment and 4 and 28 weeks after \ntreatment initiation. Follow-up was completed after 6 months.\nINTERVENTION: Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly \nthereafter.\nMAIN OUTCOMES AND MEASURES: The primary outcome was to determine the changes in \nexpression of proinflammatory innate and T-cell-derived cytokines during \nustekinumab therapy. The secondary objective was to evaluate the clinical and \nhistopathologic phenotype in relation to the mRNA expression profile of \nproinflammatory cytokines.\nRESULTS: In lesional PRP skin samples from a single patient, upregulated \nexpression levels were found for most proinflammatory innate cytokines, \nincluding tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1β. Among \nadaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 \ncytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who \nreceived ustekinumab showed regression of skin lesions after 2 weeks and almost \ncomplete resolution after 1 month. Clinical and histopathologic improvement \nparalleled the expression levels of TH17 cytokines but not of interferon-γ and \nTNF, which lagged behind the amelioration.\nCONCLUSIONS AND RELEVANCE: In this case report, a role of the IL-23-TH17-axis in \nPRP was identified, suggesting a shared pathogenic inflammatory pathway with \npsoriasis, despite evident clinical and histopathologic differences. In \naddition, this report provides a rationale for targeting the IL-23-TH17-pathway \nas a treatment option for refractory PRP.",
"Psoriasis is a chronic inflammatory skin condition, characterized by T-helper \n(Th) 1 and Th17 cell activation. Ustekinumab is a fully human immunoglobulin G1κ \nmonoclonal antibody that targets the common p40 subunit that is shared by both \ninterleukin (IL)-12 and IL-23, consequently inhibiting T-cell differentiation \nalong both Th1 and Th17 pathways. This is a report of two patients who developed \npsoriatic arthritis during ustekinumab treatment for psoriasis. Neither patient \nhad a personal or family history of arthritis.",
"The choice of therapeutic agents for patients with moderate-to-severe psoriasis \nhas expanded significantly in the past decade. With new understanding of the \nimmunologic basis of psoriasis, multiple new potential targets for therapy have \nbeen identified. It is likely that a series of new medications to focus on the \nnewly identified pathways is on the horizon. The first pathway targeted by new \nmedications focuses on the p40 subunit that is shared by interleukin (IL)-12 and \nIL-23. Two human anti-p40 antibodies have been used therapeutically in psoriasis \nto date, ustekinumab (CNTO-1275, Stelara, Centocor, Horsham, PA) and briakinumab \n(ABT-874, Abbott, Abbott Park, IL). Ustekinumab was recently approved by the \nUnited States Food and Drug Administration, making it the first medication \napproved in the United States to work by this pathway while briakinumab is \ncurrently in phase III clinical trials.",
"Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic \ninflammatory diseases mainly involving the axial skeleton. Pharmacological \ntreatments for AS and ax SpA usually include local glucocorticoid injections, \nNSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non \nresponders or intolerant to anti-TNFα agents, we need new therapeutic options \nfor AS and ax SpA. Areas covered: This review describes the new biological \nagents that can be used or are in development for AS or ax SpA as well as \nemerging synthetic targeted drugs. Expert opinion: Based on the rationale of the \ninvolvement of the IL-23/Th17 axis in AS, novel biological agents have been \ndeveloped and include secukinumab, an anti-IL-17A agent and ustekinumab, an \nanti-IL-23 antibody. New compounds in the class of synthetic drugs are \napremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab \ngave positive results in the treatment of AS. Ustekinumab yielded promising \nresults in AS in an open labeled study. Apremilast is not effective in AS while \nresults with kinase inhibitors are preliminary. Future studies will clarify the \nplace of secukinumab in the therapeutic management of AS, its influence on \nradiographic progression and its effects on the non radiographic form of the \ndisease.",
"BACKGROUND & AIMS: Interleukin-12 and interleukin-23 are inflammatory cytokines \nimplicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal \nantibody against the p40 subunit of interleukin-12/23.\nMETHODS: We performed a double-blind, cross-over trial of the clinical effects \nof ustekinumab in 104 patients with moderate-to-severe Crohn's disease \n(population 1). Patients were given subcutaneous placebo at weeks 0-3, then \nustekinumab at weeks 8-11; subcutaneous ustekinumab at weeks 0-3, then placebo \nat weeks 8-11; intravenous placebo at week 0, then ustekinumab at week 8; or \nintravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an \nopen-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 \nintravenous infusion of ustekinumab in 27 patients who were primary or secondary \nnonresponders to infliximab (population 2).\nRESULTS: In population 1, clinical response rates for the combined groups given \nustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and \n6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 \npatients who were previously given infliximab (neither primary nor secondary \nnonresponders), clinical response to ustekinumab was significantly greater than \nthe group given placebo (P < .05) through week 8. In population 2, the clinical \nresponses at week 8 to subcutaneous and intravenous ustekinumab were 43% and \n54%, respectively. There was no increase in the number of adverse or serious \nadverse events in patients given ustekinumab through week 8 compared with \nplacebo.\nCONCLUSIONS: Ustekinumab induced a clinical response in patients with \nmoderate-to-severe Crohn's disease, especially in patients previously given \ninfliximab.",
"The recognition of the roles of interleukins (IL)-12 and IL-23 in the \ndevelopment of psoriasis is an important advance in the understanding, and the \nsubsequent management, of this chronic inflammatory disease. Two human anti-p40 \nmonoclonal antibodies targeting both IL-12 and IL-23 via their shared p40 \nsubunit have been developed: briakinumab and ustekinumab. Recent Phase 2 and \nPhase 3 trials have illustrated the benefits of briakinumab (in Phase 3 clinical \ndevelopment) and ustekinumab (approved in the EU, and also in other territories \nworldwide) in the treatment of moderate to severe plaque psoriasis. Available \ndata indicate that a strategy targeting the IL-12 p40 subunit has considerable \nadvantages over targeting of tumour necrosis factor-α, offering rapid onset of \nefficacy with a favourable dosing regimen (every 12 weeks for ustekinumab). \nRegistries incorporating rigorous pharmacovigilance are now required to further \nunderstand the clinical profile of these drugs over long-term use."
] | nan |
5c7036127c78d69471000064 | [
30140466,
29976469,
25626182
] | train | Which two surgical methods were compared in the RAZOR trial? | list | The RAZOR trial compared open radical cystectomy vs. robot-assisted radical cystectomy in patients with bladder cancer. | ['open radical cystectomy', 'robot-assisted radical cystectomy'] | [
"OBJECTIVE: To investigate whether a totally intracorporeally radical cystectomy \n(RC) can be considered the new 'gold standard' in bladder cancer, as open RC \n(ORC) is the current 'gold standard' for surgical treatment of muscle-invasive \nand high-grade non-muscle-invasive bladder cancer. However, robot-assisted \nradical cystectomy (RARC) is becoming the preferred surgical approach in many \ncentres as it seems to maintain the oncological control of open surgery whilst \noffering improved perioperative benefits.\nMATERIALS AND METHODS: A review of the literature was conducted using the \nPubmed/MEDLINE, ISI Web of Knowledge and Cochrane Databases to identify studies \nthat included both ORC and RARC with intracorporeal and extracorporeal urinary \ndiversion (UD) published up to July 2017.\nRESULTS: Evidence from four single-centre randomised controlled trials and now \nthe multicentre Randomized Trial of Open versus Robotic Cystectomy (RAZOR) trial \ndemonstrate the oncological equivalence of RARC to ORC. The only convincing \nevidence for the superiority of RARC is in the area of blood loss and \ntransfusion rates. However, the UD procedure in these trials was performed \nextracorporeally and, to realise the full benefits of RARC, a totally \nintracorporeal approach is needed. Intracorporeal UDs (ICUDs) have been shown to \nbe technically feasible by a few expert centres and have demonstrated some \nimproved short-term perioperative outcomes compared to extracorporeal UDs.\nCONCLUSIONS: Although initial outcomes appear promising, RARC with ICUD is far \nfrom gaining 'gold standard' status. Further studies are needed to confirm that \noutcomes are reproducible widely. Furthermore, the benefits of a totally \nintracorporeal approach must be confirmed in randomised controlled trials.",
"BACKGROUND: Radical cystectomy is the surgical standard for invasive bladder \ncancer. Robot-assisted cystectomy has been proposed to provide similar \noncological outcomes with lower morbidity. We aimed to compare progression-free \nsurvival in patients with bladder cancer treated with open cystectomy and \nrobot-assisted cystectomy.\nMETHODS: The RAZOR study is a randomised, open-label, non-inferiority, phase 3 \ntrial done in 15 medical centres in the USA. Eligible participants (aged ≥18 \nyears) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or \nrefractory carcinoma in situ. Individuals who had previously had open abdominal \nor pelvic surgery, or who had any pre-existing health conditions that would \npreclude safe initiation or maintenance of pneumoperitoneum were excluded. \nPatients were centrally assigned (1:1) via a web-based system, with block \nrandomisation by institution, stratified by type of urinary diversion, clinical \nT stage, and Eastern Cooperative Oncology Group performance status, to receive \nrobot-assisted radical cystectomy or open radical cystectomy with extracorporeal \nurinary diversion. Treatment allocation was only masked from pathologists. The \nprimary endpoint was 2-year progression-free survival, with non-inferiority \nestablished if the lower bound of the one-sided 97·5% CI for the treatment \ndifference (robotic cystectomy minus open cystectomy) was greater than -15 \npercentage points. The primary analysis was done in the per-protocol population. \nSafety was assessed in the same population. This trial is registered with \nClinicalTrials.gov, number NCT01157676.\nFINDINGS: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly \nassigned to treatment. The intended treatment was robotic cystectomy in 176 \npatients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the \nrobotic cystectomy group did not have surgery and nine (5%) patients had a \ndifferent surgery to that they were assigned. 21 (12%) of 174 patients in the \nopen cystectomy group did not have surgery and one (1%) patient had robotic \ncystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic \ncystectomy group and 152 in the open cystectomy group) were included in the \nper-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI \n64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in \nthe open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; \npnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. \nAdverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy \ngroup and 105 (69%) of 152 patients in the open cystectomy group. The most \ncommon adverse events were urinary tract infection (53 [35%] in the robotic \ncystectomy group vs 39 [26%] in the open cystectomy group) and postoperative \nileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open \ncystectomy group).\nINTERPRETATION: In patients with bladder cancer, robotic cystectomy was \nnon-inferior to open cystectomy for 2-year progression-free survival. Increased \nadoption of robotic surgery in clinical practice should lead to future \nrandomised trials to assess the true value of this surgical approach in patients \nwith other cancer types.\nFUNDING: National Institutes of Health National Cancer Institute.",
"The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to \ncompare open radical cystectomy (ORC) vs robot-assisted RC (RARC), pelvic lymph \nnode dissection (PLND) and urinary diversion for oncological outcomes, \ncomplications and health-related quality of life (HRQL) measures with a primary \nendpoint of 2-year progression-free survival (PFS). RAZOR is a \nmulti-institutional, randomized, non-inferior, phase III trial that will enrol \nat least 320 patients with T1-T4, N0-N1, M0 bladder cancer with ≈160 patients in \nboth the RARC and ORC arms at 15 participating institutions. Data will be \ncollected prospectively at each institution for cancer outcomes, complications \nof surgery and HRQL measures, and then submitted to trial data management \nservices Cancer Research and Biostatistics (CRAB) for final analyses. To date, \n306 patients have been randomized and accrual to the RAZOR trial is expected to \nconclude in 2014. In this study, we report the RAZOR trial experimental design, \nobjectives, data safety, and monitoring, and accrual update. The RAZOR trial is \na landmark study in urological oncology, randomizing T1-T4, N0-N1, M0 patients \nwith bladder cancer to ORC vs RARC, PLND and urinary diversion. RAZOR is a \nmulti-institutional, non-inferiority trial evaluating cancer outcomes, surgical \ncomplications and HRQL measures of ORC vs RARC with a primary endpoint of 2-year \nPFS. Full data from the RAZOR trial are not expected until 2016-2017."
] | nan |
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] | train | Which type of GTPases is required for amino acid-dependent activation of mTORC1? | factoid | Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome | Heterodimeric Rag GTPases | [
"mTORC1 is essential for regulating cell growth and metabolism in response to \nvarious environmental stimuli. Heterodimeric Rag GTPases are required for \namino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by \nwhich amino acids regulate Rag activation remains not fully understood. Here, we \nidentified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential \nnegative regulator of the mTORC1 pathway by targeting RagA for K63-linked \nubiquitination. RNF152 interacts with and ubiquitinates RagA in an \namino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes \nthis effect of RNF152 and enhances the RagA-mediated activation of mTORC1. \nUbiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor \nGATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the \nhyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced \nautophagy. Thus, this study reveals a mechanism for regulation of mTORC1 \nsignaling by RNF152-mediated K63-linked polyubiquitination of RagA.",
"Author information:\n(1)Whitehead Institute for Biomedical Research and Massachusetts Institute of \nTechnology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. \nHoward Hughes Medical Institute, Department of Biology, Massachusetts Institute \nof Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer \nResearch, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of \nHarvard and Massachusetts Institute of Technology, 7 Cambridge Center, \nCambridge, MA 02142, USA.\n(2)Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA.\n(3)Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical \nSchool, 220 Longwood Avenue, Boston, MA 02115, USA.\n(4)Whitehead Institute for Biomedical Research and Massachusetts Institute of \nTechnology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. \nHoward Hughes Medical Institute, Department of Biology, Massachusetts Institute \nof Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer \nResearch, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of \nHarvard and Massachusetts Institute of Technology, 7 Cambridge Center, \nCambridge, MA 02142, USA. sabatini@wi.mit.edu.",
"The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates \nenvironmental and intracellular signals to regulate cell growth. Amino acids \nstimulate mTORC1 activation at the lysosome in a manner thought to be dependent \non the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and \nthe vacuolar H(+)-adenosine triphosphatase (v-ATPase). We report that leucine \nand glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent \nmechanisms, respectively. Glutamine promoted mTORC1 translocation to the \nlysosome in RagA and RagB knockout cells and required the v-ATPase but not the \nRagulator. Furthermore, we identified the adenosine diphosphate ribosylation \nfactor-1 GTPase to be required for mTORC1 activation and lysosomal localization \nby glutamine. Our results uncover a signaling cascade to mTORC1 activation \nindependent of the Rag GTPases and suggest that mTORC1 is differentially \nregulated by specific amino acids.",
"The signaling adaptor p62 is a critical mediator of important cellular \nfunctions, owing to its ability to establish interactions with various signaling \nintermediaries. Here, we identify raptor as an interacting partner of p62. Thus, \np62 is an integral part of the mTORC1 complex and is necessary to mediate amino \nacid signaling for the activation of S6K1 and 4EBP1. p62 interacts in an amino \nacid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags \nproteins and favors formation of the active Rag heterodimer that is further \nstabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal \ncompartment and is required for the interaction of mTOR with Rag GTPases in vivo \nand for translocation of the mTORC1 complex to the lysosome, a crucial step for \nmTOR activation.",
"Author information:\n(1)Department of Biology, Whitehead Institute for Biomedical Research and \nMassachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, \nUSA; Department of Biology, Howard Hughes Medical Institute, Massachusetts \nInstitute of Technology, Cambridge, MA 02139, USA; Koch Institute for \nIntegrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; \nBroad Institute of Harvard and Massachusetts Institute of Technology, 7 \nCambridge Center, Cambridge MA 02142, USA.\n(2)Department of Biology, Whitehead Institute for Biomedical Research and \nMassachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, \nUSA; Department of Biology, Howard Hughes Medical Institute, Massachusetts \nInstitute of Technology, Cambridge, MA 02139, USA.\n(3)Department of Biology, Whitehead Institute for Biomedical Research and \nMassachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, \nUSA.\n(4)Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, \nBoston, MA 02115, USA.\n(5)Department of Biology, Whitehead Institute for Biomedical Research and \nMassachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, \nUSA; Department of Biology, Howard Hughes Medical Institute, Massachusetts \nInstitute of Technology, Cambridge, MA 02139, USA; Koch Institute for \nIntegrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; \nBroad Institute of Harvard and Massachusetts Institute of Technology, 7 \nCambridge Center, Cambridge MA 02142, USA. Electronic address: \nsabatini@wi.mit.edu.",
"Activation of mammalian target of rapamycin complex 1 (mTORC1) by amino acids is \nmediated in part by the Rag GTPases, which bind the raptor subunit of mTORC1 in \nan amino acid-stimulated manner and promote mTORC1 interaction with Rheb-GTP, \nthe immediate activator. Here we examine whether the ability of amino acids to \nregulate mTORC1 binding to Rag and mTORC1 activation is due to the regulation of \nRag guanyl nucleotide charging. Rag heterodimers in vitro exhibit a very rapid, \nspontaneous exchange of guanyl nucleotides and an inability to hydrolyze GTP. \nMutation of the Rag P-loop corresponding to Ras(Ser-17) abolishes guanyl \nnucleotide binding. Such a mutation in RagA or RagB inhibits, whereas in RagC or \nRagD it enhances, Rag heterodimer binding to mTORC1. The binding of wild-type \nand mutant Rag heterodimers to mTORC1 in vitro parallels that seen with \ntransient expression, but binding to mTORC1 in vitro is entirely independent of \nRag guanyl nucleotide charging. HeLa cells stably overexpressing wild-type or \nP-loop mutant RagC exhibit unaltered amino acid regulation of mTORC1. Despite \namino acid-independent raptor binding to Rag, mTORC1 is inhibited by amino acid \nwithdrawal as in parental cells. Rag heterodimers extracted from (32)P-labeled \nwhole cells, or just from the pool associated with the lysosomal membrane, \nexhibit constitutive [(32)P]GTP charging that is unaltered by amino acid \nwithdrawal. Thus, amino acids promote mTORC1 activation without altering Rag GTP \ncharging. Raptor binding to Rag, although necessary, is not sufficient for \nmTORC1 activation. Additional amino acid-dependent steps couple Rag-mTORC1 to \nRheb-GTP.",
"The mTORC1 kinase is a master growth regulator that senses numerous \nenvironmental cues, including amino acids. The Rag GTPases interact with mTORC1 \nand signal amino acid sufficiency by promoting the translocation of mTORC1 to \nthe lysosomal surface, its site of activation. The Rags are unusual GTPases in \nthat they function as obligate heterodimers, which consist of RagA or B bound \nto RagC or D. While the loading of RagA/B with GTP initiates amino acid \nsignaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is \na key regulator of the interaction of mTORC1 with the Rag heterodimer and that, \nunexpectedly, RagC/D must be GDP bound for the interaction to occur. We identify \nFLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP \nactivity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 \nactivation and a molecular function for the FLCN tumor suppressor.",
"Amino acids are required for activation of the mammalian target of rapamycin \n(mTOR) kinase, which regulates protein translation, cell size, and autophagy. \nHowever, the amino acid sensor that directly couples intracellular amino \nacid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA \nsynthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation \nby sensing intracellular leucine concentration and initiating molecular events \nleading to mTORC1 activation. Mutation of LRS amino acid residues important for \nleucine binding renders the mTORC1 pathway insensitive to intracellular levels \nof amino acids. We show that LRS directly binds to Rag GTPase, the mediator of \namino acid signaling to mTORC1, in an amino acid-dependent manner and functions \nas a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This \nwork demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.",
"Birt-Hogg-Dubé syndrome, a human disease characterized by fibrofolliculomas \n(hair follicle tumors) as well as a strong predisposition toward the development \nof pneumothorax, pulmonary cysts, and renal carcinoma, arises from \nloss-of-function mutations in the folliculin (FLCN) gene. In this study, we show \nthat FLCN regulates lysosome function by promoting the mTORC1-dependent \nphosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). \nOur results indicate that FLCN is specifically required for the amino \nacid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. We further \ndemonstrated that FLCN itself was selectively recruited to the surface of \nlysosomes after amino acid depletion and directly bound to RagA via its GTPase \ndomain. FLCN-interacting protein 1 (FNIP1) promotes both the lysosome \nrecruitment and Rag interactions of FLCN. These new findings define the lysosome \nas a site of action for FLCN and indicate a critical role for FLCN in the amino \nacid-dependent activation of mTOR via its direct interaction with the RagA/B \nGTPases.",
"mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein \ncomplex regulating cell growth and metabolism via its kinase mTOR (mammalian \ntarget of rapamycin). The activity of mTOR is under the control of various \nGTPases, of which Rheb and the Rags play a central role. The presence of amino \nacids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases \nlocalize mTORC1 to lysosomes by their amino-acid-dependent interaction with the \nlysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to \nactivate mTORC1. Rheb is responsive to growth factors, but, in conjunction with \nPLD1 (phospholipase D1), is also an integral part of the machinery that \nstimulates mTORC1 in response to amino acids. In the present article, we provide \na brief overview of novel mechanisms by which amino acids affect the function of \nRags. On the basis of existing literature, we postulate that Rheb is activated \nat the Golgi from where it will travel to lysosomes. Maturation of endosomes \ninto lysosomes may be required to assure a continuous supply of GTP-bound Rheb \nfor mTORC1 activation, which may help to drive the maturation process.",
"The mechanistic target of rapamycin complex I (mTORC1) is a central regulator of \ncellular and organismal growth, and hyperactivation of this pathway is \nimplicated in the pathogenesis of many human diseases including cancer and \ndiabetes. mTORC1 promotes growth in response to the availability of nutrients, \nsuch as amino acids, which drive mTORC1 to the lysosomal surface, its site of \nactivation. How amino acid levels are communicated to mTORC1 is only recently \ncoming to light by the discovery of a lysosome-based signaling system composed \nof Rags (Ras-related GTPases) and Ragulator v-ATPase, GATOR (GAP activity \ntowards Rags), and folliculin (FLCN) complexes. Increased understanding of this \npathway will not only provide insight into growth control but also into the \nhuman pathologies triggered by its deregulation."
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] | train | Which type of analysis does DeSeq2 perform? | factoid | DeSeq2 is a software for differential gene expression analysis of RNA sequencing data. | differential analysis of RNASeq data | [
"BACKGROUND: Several R packages exist for the detection of differentially \nexpressed genes from RNA-Seq data. The analysis process includes three main \nsteps, namely normalization, dispersion estimation and test for differential \nexpression. Quality control steps along this process are recommended but not \nmandatory, and failing to check the characteristics of the dataset may lead to \nspurious results. In addition, normalization methods and statistical models are \nnot exchangeable across the packages without adequate transformations the users \nare often not aware of. Thus, dedicated analysis pipelines are needed to include \nsystematic quality control steps and prevent errors from misusing the proposed \nmethods.\nRESULTS: SARTools is an R pipeline for differential analysis of RNA-Seq count \ndata. It can handle designs involving two or more conditions of a single \nbiological factor with or without a blocking factor (such as a batch effect or a \nsample pairing). It is based on DESeq2 and edgeR and is composed of an R package \nand two R script templates (for DESeq2 and edgeR respectively). Tuning a small \nnumber of parameters and executing one of the R scripts, users have access to \nthe full results of the analysis, including lists of differentially expressed \ngenes and a HTML report that (i) displays diagnostic plots for quality control \nand model hypotheses checking and (ii) keeps track of the whole analysis \nprocess, parameter values and versions of the R packages used.\nCONCLUSIONS: SARTools provides systematic quality controls of the dataset as \nwell as diagnostic plots that help to tune the model parameters. It gives access \nto the main parameters of DESeq2 and edgeR and prevents untrained users from \nmisusing some functionalities of both packages. By keeping track of all the \nparameters of the analysis process it fits the requirements of reproducible \nresearch.",
"Background. A common research goal in transcriptome projects is to find genes \nthat are differentially expressed in different phenotype classes. Biologists \nmight wish to validate such gene candidates experimentally, or use them for \ndownstream systems biology analysis. Producing a coherent differential gene \nexpression analysis from RNA-seq count data requires an understanding of how \nnumerous sources of variation such as the replicate size, the hypothesized \nbiological effect size, and the specific method for making differential \nexpression calls interact. We believe an explicit demonstration of such \ninteractions in real RNA-seq data sets is of practical interest to biologists. \nResults. Using two large public RNA-seq data sets-one representing strong, and \nanother mild, biological effect size-we simulated different replicate size \nscenarios, and tested the performance of several commonly-used methods for \ncalling differentially expressed genes in each of them. We found that, when \nbiological effect size was mild, RNA-seq experiments should focus on \nexperimental validation of differentially expressed gene candidates. \nImportantly, at least triplicates must be used, and the differentially expressed \ngenes should be called using methods with high positive predictive value (PPV), \nsuch as NOISeq or GFOLD. In contrast, when biological effect size was strong, \ndifferentially expressed genes mined from unreplicated experiments using NOISeq, \nASC and GFOLD had between 30 to 50% mean PPV, an increase of more than 30-fold \ncompared to the cases of mild biological effect size. Among methods with good \nPPV performance, having triplicates or more substantially improved mean PPV to \nover 90% for GFOLD, 60% for DESeq2, 50% for NOISeq, and 30% for edgeR. At a \nreplicate size of six, we found DESeq2 and edgeR to be reasonable methods for \ncalling differentially expressed genes at systems level analysis, as their PPV \nand sensitivity trade-off were superior to the other methods'. Conclusion. When \nbiological effect size is weak, systems level investigation is not possible \nusing RNAseq data, and no meaningful result can be obtained in unreplicated \nexperiments. Nonetheless, NOISeq or GFOLD may yield limited numbers of gene \ncandidates with good validation potential, when triplicates or more are \navailable. When biological effect size is strong, NOISeq and GFOLD are effective \ntools for detecting differentially expressed genes in unreplicated RNA-seq \nexperiments for qPCR validation. When triplicates or more are available, GFOLD \nis a sharp tool for identifying high confidence differentially expressed genes \nfor targeted qPCR validation; for downstream systems level analysis, combined \nresults from DESeq2 and edgeR are useful.",
"Circulating miRNAs have received extensive attention as non-invasive biomarkers \nfor prediction and diagnosis of disease. However, most samples have been \nobtained from peripheral venous blood. To evaluate whether peripheral venous \nmiRNAs represent circulating miRNAs from all blood vessels under a given \ncondition, such as aging, we compared the miRNA profiles of venous and arterial \nplasma between young and aged rats by Illumina next-generation sequencing. The \nDEseq2 tool was used to obtain differentially-expressed miRNAs. We observed 105 \naging-related deregulated miRNAs in vein and 62 in artery, which were highly \nassociated with cell survival and inflammation, respectively. On the other hand, \nthe young and aged groups exhibited a unique arterial-venous bias. There were 54 \ndifferentially-expressed miRNAs in the young group and 42 in the aged group; \nonly 8 miRNAs were shared. Further transcriptional factors enrichment analysis \nfound that the shared miRNAs could be partially upregulated by NF-κB and SIRT1. \nThese transcriptional factors could be organ-specific and/or regulated in \nphysiological and aging states as possible causal factors. This study suggested \nthe potential application of circulating miRNAs, which reflect the systematic \nresponse to certain conditions, such as aging, and the importance of origin \nselection for candidate circulating miRNAs.",
"Meat color is considered to be the most important indicator of meat quality, \nhowever, the molecular mechanisms underlying traits related to meat color remain \nmostly unknown. In this study, to elucidate the molecular basis of meat color, \nwe constructed six cDNA libraries from biceps femoris (Bf) and soleus (Sol), \nwhich exhibit obvious differences in meat color, and analyzed the \nwhole-transcriptome differences between Bf (white muscle) and Sol (red muscle) \nusing high-throughput sequencing technology. Using DEseq2 method, we identified \n138 differentially expressed genes (DEGs) between Bf and Sol. Using DEGseq \nmethod, we identified 770, 810, and 476 DEGs in comparisons between Bf and Sol \nin three separate animals. Of these DEGs, 52 were overlapping DEGs. Using these \ndata, we determined the enriched GO terms, metabolic pathways and candidate \ngenes associated with meat color traits. Additionally, we mapped 114 \nnon-redundant DEGs to the meat color QTLs via a comparative analysis with the \nporcine quantitative trait loci (QTL) database. Overall, our data serve as a \nvaluable resource for identifying genes whose functions are critical for meat \ncolor traits and can accelerate studies of the molecular mechanisms of meat \ncolor formation.",
"Brain gene expression profiling studies of suicide and depression using \noligonucleotide microarrays have often failed to distinguish these two \nphenotypes. Moreover, next generation sequencing approaches are more accurate in \nquantifying gene expression and can detect alternative splicing. Using RNA-seq, \nwe examined whole-exome gene and exon expression in non-psychiatric controls \n(CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD \nnon-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area \n9) of sudden death medication-free individuals post mortem. Using small RNA-seq, \nwe also examined miRNA expression (nine samples per group). DeSeq2 identified 35 \ngenes differentially expressed between groups and surviving adjustment for false \ndiscovery rate (adjusted P<0.1). In depression, altered genes include \nhumanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, \nclade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene \nontology (GO) analyses revealed lower expression of immune-related pathways such \nas chemokine receptor activity, chemotaxis and cytokine biosynthesis, and \nangiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO \nanalysis suggests lower expression of genes involved in oligodendrocyte \ndifferentiation, regulation of glutamatergic neurotransmission, and oxytocin \nreceptor expression in both suicide and depression, and provisional evidence for \naltered DNA-dependent ATPase expression in suicide only. DEXSEq analysis \nidentified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) \nin depression. Differences in miRNA expression or structural gene variants were \nnot detected. Results lend further support for models in which deficits in \nmicroglial, endothelial (blood-brain barrier), ATPase activity and astrocytic \ncell functions contribute to MDD and suicide, and identify putative pathways and \nmechanisms for further study in these disorders.",
"The rapid expansion of transcriptomics and affordability of next-generation \nsequencing (NGS) technologies generate rocketing amounts of gene expression data \nacross biology and medicine, including cancer research. Concomitantly, many \nbioinformatics tools were developed to streamline gene expression and \nquantification. We tested the concordance of NGS RNA sequencing (RNA-seq) \nanalysis outcomes between two predominant programs for read alignment, HISAT2, \nand STAR, and two most popular programs for quantifying gene expression in NGS \nexperiments, edgeR and DESeq2, using RNA-seq data from breast cancer progression \nseries, which include histologically confirmed normal, early neoplasia, ductal \ncarcinoma in situ and infiltrating ductal carcinoma samples microdissected from \nformalin fixed, paraffin embedded (FFPE) breast tissue blocks. We identified \nsignificant differences in aligners' performance: HISAT2 was prone to misalign \nreads to retrogene genomic loci, STAR generated more precise alignments, \nespecially for early neoplasia samples. edgeR and DESeq2 produced similar lists \nof differentially expressed genes, with edgeR producing more conservative, \nthough shorter, lists of genes. Gene Ontology (GO) enrichment analysis revealed \nno skewness in significant GO terms identified among differentially expressed \ngenes by edgeR versus DESeq2. As transcriptomics of FFPE samples becomes a \nvanguard of precision medicine, choice of bioinformatics tools becomes critical \nfor clinical research. Our results indicate that STAR and edgeR are well-suited \ntools for differential gene expression analysis from FFPE samples.",
"myPhyloDB v.1.1.2 is a user-friendly personal database with a browser-interface \ndesigned to facilitate the storage, processing, analysis, and distribution of \nmicrobial community populations (e.g. 16S metagenomics data). MyPhyloDB archives \nraw sequencing files, and allows for easy selection of project(s)/sample(s) of \nany combination from all available data in the database. The data processing \ncapabilities of myPhyloDB are also flexible enough to allow the upload and \nstorage of pre-processed data, or use the built-in Mothur pipeline to automate \nthe processing of raw sequencing data. myPhyloDB provides several analytical \n(e.g. analysis of covariance,t-tests, linear regression, differential abundance \n(DESeq2), and principal coordinates analysis (PCoA)) and normalization \n(rarefaction, DESeq2, and proportion) tools for the comparative analysis of \ntaxonomic abundance, species richness and species diversity for projects of \nvarious types (e.g. human-associated, human gut microbiome, air, soil, and \nwater) for any taxonomic level(s) desired. Finally, since myPhyloDB is a local \nweb-server, users can quickly distribute data between colleagues and end-users \nby simply granting others access to their personal myPhyloDB database. myPhyloDB \nis available \nathttp://www.ars.usda.gov/services/software/download.htm?softwareid=472 and more \ninformation along with tutorials can be found on our \nwebsitehttp://www.myphylodb.org. Database URL:http://www.myphylodb.org.",
"BACKGROUND: Differential expression (DE) analysis of RNA-seq data still poses \ninferential challenges, such as handling of transcripts characterized by low \nexpression levels. In this study, we use a plasmode-based approach to assess the \nrelative performance of alternative inferential strategies on RNA-seq \ntranscripts, with special emphasis on transcripts characterized by a small \nnumber of read counts, so-called low-count transcripts, as motivated by an \necological application in prairie grasses. Big bluestem (Andropogon gerardii) is \na wide-ranging dominant prairie grass of ecological and agricultural importance \nto the US Midwest while edaphic subspecies sand bluestem (A. gerardii ssp. \nHallii) grows exclusively on sand dunes. Relative to big bluestem, sand bluestem \nexhibits qualitative phenotypic divergence consistent with enhanced drought \ntolerance, plausibly associated with transcripts of low expression levels. Our \ndataset consists of RNA-seq read counts for 25,582 transcripts (60% of which are \nclassified as low-count) collected from leaf tissue of individual plants of big \nbluestem (n = 4) and sand bluestem (n = 4). Focused on low-count transcripts, we \ncompare alternative ad-hoc data filtering techniques commonly used in RNA-seq \npipelines and assess the inferential performance of recently developed \nstatistical methods for DE analysis, namely DESeq2 and edgeR robust. These \nmethods attempt to overcome the inherently noisy behavior of low-count \ntranscripts by either shrinkage or differential weighting of observations, \nrespectively.\nRESULTS: Both DE methods seemed to properly control family-wise type 1 error on \nlow-count transcripts, whereas edgeR robust showed greater power and DESeq2 \nshowed greater precision and accuracy. However, specification of the degree of \nfreedom parameter under edgeR robust had a non-trivial impact on inference and \nshould be handled carefully. When properly specified, both DE methods showed \noverall promising inferential performance on low-count transcripts, suggesting \nthat ad-hoc data filtering steps at arbitrary expression thresholds may be \nunnecessary. A note of caution is in order regarding the approximate nature of \nDE tests under both methods.\nCONCLUSIONS: Practical recommendations for DE inference are provided when \nlow-count RNA-seq transcripts are of interest, as is the case in the comparison \nof subspecies of bluestem grasses. Insights from this study may also be relevant \nto other applications focused on transcripts of low expression levels.",
"Tg26 mice are robust models of human immunodeficiency virus 1 associated \nnephropathy (HIVAN). These mice are useful for HIVAN pathology analysis, and \nrecent studies suggest that the Tg26 mouse model is an excellent model of other \nchronic kidney diseases. We performed RNA seq analysis of differential gene \nexpression in the kidneys of Tg26 mice. Kidneys were collected from Tg26 mice \nand wildtype (WT) littermates at 3 months of age. The raw data were analyzed for \ndifferential gene expression using a negative binomial generalized linear model \nin the DeSeq2 software package. We used P-Value ≤0.05 and an absolute fold \nchange of 1.5 to identify top 50 upregulated and top 50 downregulated \ndifferentially expressed genes between the WT and Tg26 mice. As expected \ninflammatory genes were among the top differentially regulated genes. Our data \nprovides yet another level of information to help gain a more comprehensive \nunderstanding of disease progression and identify potential drug targets for \nHIVAN and chronic kidney diseases.",
"RNA-Seq examines global gene expression to provide insights into cellular \nprocesses, and it can be particularly informative when comparing contrasting \nphysiological states or strains. Although relatively routine in many \nlaboratories, there are many steps involved in performing a transcriptomics \nexperiment to ensure representative and high-quality results are generated for \nanalysis. In this chapter, we present the application of widely used \nbioinformatic methodologies to assess, trim, and filter RNA-seq reads for \nquality using FastQC and Trim Galore, respectively. High-quality reads are \nmapped using Bowtie2 and differentially expressed genes across different groups \nwere estimated using the DEseq2 R-Bioconductor package. In addition, we describe \nthe various steps to perform the sample-wise data quality assessment by \ngenerating exploratory plots through the DESeq2 package. Simple steps to \ncalculate the significant differentially expressed genes, up- and down-regulated \ngenes, and exporting the data and images are also included. A Venn diagram is a \nuseful method to compare the differentially expressed genes across various \ncomparisons and steps to generate the Venn diagram from DESeq2 results are \nprovided. Finally, the output from DESeq2 is compared to published results from \nEdgeR. The Clostridium autoethanogenum data are published and publicly \navailable.",
"In the past 5 years, RNA-Seq has become a powerful tool in transcriptome \nanalysis even though computational methods dedicated to the analysis of \nhigh-throughput sequencing data are yet to be standardized. It is, however, now \ncommonly accepted that the choice of a normalization procedure is an important \nstep in such a process, for example in differential gene expression analysis. \nThe present article highlights the similarities between three normalization \nmethods: TMM from edgeR R package, RLE from DESeq2 R package, and MRN. Both TMM \nand DESeq2 are widely used for differential gene expression analysis. This paper \nintroduces properties that show when these three methods will give exactly the \nsame results. These properties are proven mathematically and illustrated by \nperforming in silico calculations on a given RNA-Seq data set.",
"Cardiovascular disease accounts for millions of deaths each year and is \ncurrently the leading cause of mortality worldwide. The aging process is clearly \nlinked to cardiovascular disease, however, the exact relationship between aging \nand heart function is not fully understood. Furthermore, a holistic view of \ncardiac aging, linking features of early life development to changes observed in \nold age, has not been synthesized. Here, we re-purpose RNA-sequencing data \npreviously-collected by our group, investigating gene expression differences \nbetween wild-type mice of different age groups that represent key developmental \nmilestones in the murine lifespan. DESeq2's generalized linear model was applied \nwith two hypothesis testing approaches to identify differentially-expressed (DE) \ngenes, both between pairs of age groups and across mice of all ages. Pairwise \ncomparisons identified genes associated with specific age transitions, while \ncomparisons across all age groups identified a large set of genes associated \nwith the aging process more broadly. An unsupervised machine learning approach \nwas then applied to extract common expression patterns from this set of \nage-associated genes. Sets of genes with both linear and non-linear expression \ntrajectories were identified, suggesting that aging not only involves the \nactivation of gene expression programs unique to different age groups, but also \nthe re-activation of gene expression programs from earlier ages. Overall, we \npresent a comprehensive transcriptomic analysis of cardiac gene expression \npatterns across the entirety of the murine lifespan.",
"The current DNA sequencing technologies and their high-throughput yield, allowed \nthe thrive of genomic and transcriptomic experiments but it also have generated \nbig data problem. Due to this exponential growth of sequencing data, also the \ncomplexity of managing, processing and interpreting it in order to generate \nresults, has raised. Therefore, the demand of easy-to-use friendly software and \nwebsites to run bioinformatic tools is imminent. In particular, RNA-Seq and \ndifferential expression analysis have become a popular and useful method to \nevaluate the genetic expression change in any organism. However, many scientists \nstruggle with the data analysis since most of the available tools are \nimplemented in a UNIX-based environment. Therefore, we have developed the web \nserver IDEAMEX (Integrative Differential Expression Analysis for Multiple \nEXperiments). The IDEAMEX pipeline needs a raw count table for as many desired \nreplicates and conditions, allowing the user to select which conditions will be \ncompared, instead of doing all-vs.-all comparisons. The whole process consists \nof three main steps (1) Data Analysis: that allows a preliminary analysis for \nquality control based on the data distribution per sample, using different types \nof graphs; (2) Differential expression: performs the differential expression \nanalysis with or without batch effect error awareness, using the bioconductor \npackages, NOISeq, limma-Voom, DESeq2 and edgeR, and generate reports for each \nmethod; (3) Result integration: the obtained results the integrated results are \nreported using different graphical outputs such as correlograms, heatmaps, Venn \ndiagrams and text lists. Our server allows an easy and friendly visualization \nfor results, providing an easy interaction during the analysis process, as well \nas error tracking and debugging by providing output log files. The server is \ncurrently available and can be accessed at http://www.uusmb.unam.mx/ideamex/ \nwhere the documentation and example input files are provided. We consider that \nthis web server can help other researchers with no previous bioinformatic \nknowledge, to perform their analyses in a simple manner.",
"In comparative high-throughput sequencing assays, a fundamental task is the \nanalysis of count data, such as read counts per gene in RNA-seq, for evidence of \nsystematic changes across experimental conditions. Small replicate numbers, \ndiscreteness, large dynamic range and the presence of outliers require a \nsuitable statistical approach. We present DESeq2, a method for differential \nanalysis of count data, using shrinkage estimation for dispersions and fold \nchanges to improve stability and interpretability of estimates. This enables a \nmore quantitative analysis focused on the strength rather than the mere presence \nof differential expression. The DESeq2 package is available at \nhttp://www.bioconductor.org/packages/release/bioc/html/DESeq2.html webcite.",
"Background: Melanoma is highly immunogenic and therefore suitable for \nimmunotherapy, but the efficacy is limited by response rate. In several types of \ntumor, tumor mutation burden (TMB) and immune infiltration have been reported to \npredict the response to immunotherapy, although each has its limitations. In the \ncurrent study, we aimed to explore the association of TMB with immune \ninfiltration and prognosis in cutaneous melanoma. Methods: The data of cutaneous \nmelanoma used for analyses was downloaded from The Cancer Genome Atlas (TCGA) \ndatabase. The mutation data was sorted using \"maftools\" R package. TMB was \nestimated and then patients were divided into two groups based on TMB. The \nassociation of TMB with prognosis and clinical characteristics was explored. \nDifferential analysis between two TMB groups was performed using \"DESeq2\" R \npackage to identify differentially expressed genes (DEGs). The function \nenrichment analyses of DEGs were conducted to screen critical pathways. Besides, \nDEGs were further filtered to identify two hub genes, based on which a risk \nscore model and nomogram for predicting prognosis were conducted, and the \nvalidation was performed using three datasets from Gene Expression Omnibus (GEO) \ndatabase. Finally, CIBERSORT algorithm and TIMER database were used to assess \nthe effect of TMB and hub genes on immune infiltration. Results: The most common \nmutation was C > T, and the top three frequently mutated genes were TTN, MUC16, \nand BRAF. Higher TMB indicated better survival outcomes and lower pathological \nstages. 735 DEGs were identified and mainly involved in immune-related and \nadhesion-related pathways. The risk score model and nomogram were validated \nusing receiver operating characteristic (ROC) curves and calibration curves, and \nexhibited relatively high predictive capability. Decision curve analysis (DCA) \nwas used to assess clinical benefit. As for immune infiltration, the proportion \nwas higher for macrophages M1 and M2 in the high-TMB group, while lower for \nmemory B cells and regulatory T cells. Conclusions: In cutaneous melanoma, TMB \nwas positively correlated with prognosis. The risk score model and nomogram can \nbe conveniently used to predict prognosis. The association of TMB with immune \ninfiltration can help improve the predicting methods for the response to \nimmunotherapy."
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] | train | Which type of cell death is known as anoikis? | summary | Anoikis (Greek for Homelessness) is a programmed cell death induced upon cell detachment from extracellular matrix, behaving as a critical mechanism in preventing adherent-independent cell growth and attachment to an inappropriate matrix, thus avoiding colonizing of distant organs. Anoikis is important in the normal physiologic development of the human body, as well as in disease states. Adhesion to structural glycoproteins of the extracellular matrix is necessary for survival of the differentiated adherent cells. Cancer cells harbor anoikis resistance allowing spread to occur. | Anoikis (Greek for Homelessness) is a programmed cell death induced upon cell detachment from extracellular matrix, behaving as a critical mechanism in preventing adherent-independent cell growth and attachment to an inappropriate matrix, thus avoiding colonizing of distant organs. Anoikis is important in the normal physiologic development of the human body, as well as in disease states. Adhesion to structural glycoproteins of the extracellular matrix is necessary for survival of the differentiated adherent cells. Cancer cells harbor anoikis resistance allowing spread to occur. | [
"Anoikis is a programmed cell death induced upon cell detachment from \nextracellular matrix, behaving as a critical mechanism in preventing \nadherent-independent cell growth and attachment to an inappropriate matrix, thus \navoiding colonizing of distant organs. As anchorage-independent growth and \nepithelial-mesenchymal transition, two features associated with anoikis \nresistance, are vital steps during cancer progression and metastatic \ncolonization, the ability of cancer cells to resist anoikis has now attracted \nmain attention from the scientific community. Cancer cells develop anoikis \nresistance due to several mechanisms, including change in integrins' repertoire \nallowing them to grow in different niches, activation of a plethora of \ninside-out pro-survival signals as over-activation of receptors due to sustained \nautocrine loops, oncogene activation, growth factor receptor overexpression, or \nmutation/upregulation of key enzymes involved in integrin or growth factor \nreceptor signaling. In addition, tumor microenvironment has also been \nacknowledged to contribute to anoikis resistance of bystander cancer cells, by \nmodulating matrix stiffness, enhancing oxidative stress, producing pro-survival \nsoluble factors, triggering epithelial-mesenchymal transition and self-renewal \nability, as well as leading to metabolic deregulations of cancer cells. All \nthese events help cancer cells to inhibit the apoptosis machinery and sustain \npro-survival signals after detachment, counteracting anoikis and constituting \npromising targets for anti-metastatic pharmacological therapy. This article is \npart of a Special Section entitled: Cell Death Pathways.",
"Anoikis is a mode of apoptotic cell death, consequential to insufficient \ncell-matrix interactions and a critical player in tumor angiogenesis and \nmetastasis. The events involved in tumor cell progression toward metastasis \npotential are mediated by integrins, which upon engagement with components of \nthe extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting \napoptotic players is of immense therapeutic significance since resistance to \napoptosis is not only critical in conferring therapeutic failure to standard \ntreatment strategies, but anoikis (apoptosis upon loss of anchorage and \ndetachment from ECM) also plays an important role in angiogenesis and \nmetastasis. The ability to survive in the absence of adhesion to the ECM, \nenables tumor cells to disseminate from the primary tumor site, invade a distant \nsite and establish a metastatic lesion. Tumor cells can escape from \ndetachment-induced apoptosis by controlling anoikis pathways, including the \nextrinsic death receptor pathway and the ECM-integrin mediated cell survival \npathway. Considering the functional promiscuity of individual signaling \neffectors, it is critical to dissect the molecular networks mechanistically \ndriving tumor cells to evade anoikis and embark on a metastatic spread. \nResistance to die via anoikis dictates tumor cell survival and provides a \nmolecular basis for therapeutic targeting of metastatic prostate cancer. Further \ndissection of critical anoikis signaling events will enable the therapeutic \noptimization of anoikis targeting to impair prostate cancer metastasis prior to \nits initiation. This review will discuss the molecular understanding of anoikis \nregulation in the tumor microenvironment and the in vivo pharmacological \nimplementation of a novel class of antitumor-drugs to optimize apoptotic-based \ntherapeutic targeting, bypassing anoikis-resistance to impair prostate cancer \nprogression to metastasis. Potential combination strategies targeting tumor \nvascularity (via anoikis) and impairing tumor initiation (via \"classic\" \napoptosis), provide strong therapeutic promise for metastatic prostate cancer by \npreventing the onset of metastasis.",
"Developed organs display strict spatial organization of differentiated cells \nwhich is required for proper organ function. One important device that prevents \ntissue disorganization is the death of cells that lose anchorage to their native \nmatrix, a signal that indicates potential loss of proper tissue context. Termed \nanoikis (Greek for Homelessness), this form of cell death is a specialized form \nof apoptosis. Interestingly, at certain stages of development and tissue repair, \ncells are required to migrate in an unanchored state, suggesting that anoikis \nmust be strictly regulated at some level. Likewise, cellular transformation is \noften accompanied by an inappropriate loss of anoikis and subsequent acquisition \nof a metastatic phenotype. Despite its importance, the molecular pathways \ninvolved in the regulation of anoikis and the proximal signals reporting loss of \nanchorage are poorly understood. Recent studies suggest that attachment may be \nreported by a mechanosensory testing of the cell's physical environment.",
"BACKGROUND: Anoikis is a special type of programmed cell death after loss of \ncell-cell and cell-extracellular matrix interactions. Resistance to anoikis is \nlikely involved in the process of metastasis, specifically during the tumor cell \nmigration through lymph or vascular channels. We have previously shown that \nBCL-2 confers resistance to other forms of programmed cell death (i.e., \napoptosis); furthermore, the extracellular signaling-regulated kinase (ERK) \nsignaling pathway regulates BCL-2 expression. We therefore tested the hypothesis \nthat pancreatic cancer cell lines are resistant to anoikis and this resistance \nis due to activation of ERK1/2 and subsequent overexpression of BCL-2.\nMATERIALS AND METHODS: Pancreatic cancer cell lines (MIA-PaCa-2 and BxPC-3) were \nexamined for cell death following loss of adherence to extracellular matrix. \nSubclones of the MIA-PaCa-2 cell line (either selected in vivo for increased \nmetastatic potential [MIA-LM2] or overexpressing BCL-2 [MIA-BCL2]) were also \nexamined for induction of anoikis following loss of extracellular matrix \nadherence. Finally, the effect of the ERK inhibitor (PD98059) on BCL-2 \nexpression and induction of anoikis was examined.\nRESULTS: Under conditions of loss of cell-extracellular matrix interaction, \npancreatic cancer cells undergo varying amounts of anoikis. Basal levels of \nactivated ERK and BCL-2 paralleled the sensitivity to induction of anoikis. The \nhighly metastatic cell line, MIA-LM2, was more resistant to anoikis than the \nparental cell line. Inhibition of ERK down-regulated BCL-2 and was associated \nwith restoration of sensitivity to anoikis.\nCONCLUSIONS: Activation of a signaling pathway from ERK to overexpression of \nBCL-2 may confer resistance to anoikis, a critical step in the development of \nmetastasis. Targeting the ERK/BCL-2 pathway may lead to sensitization of \npancreatic cancer to anoikis, thereby decreasing the ability of these cells to \nmetastasize.",
"Anoikis is a type of apoptosis due to the detachment from the extracellular \nmatrix and neighboring cells. In case of cell transplantation therapy for spinal \ncord injury, preparation of graft cells includes dissociation of cultured cells, \nwhich may cause anoikis-induced cell death. Thus suppression of anoikis may \nincrease survival of grafted cells. Here we tested the effect of brain-derived \nneurotrophic factor (BDNF) on anoikis-induced cell death of cultured Schwann \ncells. Schwann cells were collected and cultured from sciatic nerves of neonatal \nWistar rats. Schwann cells were plated upon a non-adherent polyhydroxyethyl \nmethacrylate substrate to induce anoikis. BDNF was added into the culture medium \nat various concentrations. Twenty-four hours after non-adherent culture, \napproximately 40% of Schwann cells died and BDNF significantly decreased the \nnumber of dead cells in that culture condition. Next, Schwann cells were \ntransplanted with or without BDNF treatment into contused rat spinal cord 1 week \nafter injury. Five weeks after transplantation, immunohistochemistry revealed \nthat the number of transplanted cells was significantly larger in the \nBDNF-treated group than that of the non-treated group. Suppression of anoikis \nmay increase survival of grafted cells in case of cell therapy for spinal cord \ninjury.",
"Cell therapy, in particular liver cell transplantation, holds great therapeutic \npotential and is partially hindered by the high rate of apoptosis during cell \nisolation, cryopreservation and engraftment. Apoptosis triggered by cell \ndetachment from the extracellular matrix, which occurs during hepatocyte \nisolation, is a phenomenon termed \"anoikis\". It's importance in the normal \nphysiologic development of the human body, as well as in disease states, has \nbeen described. Cancer cells harbor anoikis resistance allowing spread to occur. \nActivation of the protein Fas associated death domain/MORT1 initiates the \napoptosis cascade, with further downstream activation of caspase 8, Bid, \ncytochrome c and the executioner caspases. The anti-apoptotic protein family \n(bcl-2) and integrins, in particular beta 1 integrin, balance the pro apoptotic \nsignals. The family of caspase enzymes, currently including 14 members, is \nsubdivided by the prodomain length, specific substrate and phylogenetic \nanalysis, and plays a crucial role in the apoptotic cascade. Therefore, \nunderstanding the molecular biology of apoptosis and specifically the \"form\" \ntermed anoikis, has advanced clinical implications in cancer and cell therapy \nresearch.",
"Anoikis is a programmed cell death induced upon cell detachment from \nextracellular matrix, behaving as a critical mechanism in preventing \nadherent-independent cell growth and attachment to an inappropriate matrix, thus \navoiding colonization of distant organs. Cell adhesion plays an important role \nin neoplastic transformation. Tumors produce several molecules that facilitate \ntheir proliferation, invasion and maintenance, especially proteoglycans. The \nsyndecan-4, a heparan sulfate proteoglycan, can act as a co-receptor of growth \nfactors and proteins of the extracellular matrix by increasing the affinity of \nadhesion molecules to their specific receptors. It participates together with \nintegrins in cell adhesion at focal contacts connecting the extracellular matrix \nto the cytoskeleton. Changes in the expression of syndecan-4 have been observed \nin tumor cells, indicating its involvement in cancer. This study investigates \nthe role of syndecan-4 in the process of anoikis and cell transformation. \nEndothelial cells were submitted to sequential cycles of forced anchorage \nimpediment and distinct lineages were obtained. Anoikis-resistant endothelial \ncells display morphological alterations, high rate of proliferation, poor \nadhesion to fibronectin, laminin and collagen IV and deregulation of the cell \ncycle, becoming less serum-dependent. Furthermore, anoikis-resistant cell lines \ndisplay a high invasive potential and a low rate of apoptosis. This is \naccompanied by an increase in the levels of heparan sulfate and chondroitin \nsulfate as well as by changes in the expression of syndecan-4 and heparanase. \nThese results indicate that syndecan-4 plays a important role in acquisition of \nanoikis resistance and that the conferral of anoikis resistance may suffice to \ntransform endothelial cells.",
"Anoikis is a programmed cell death occurring upon cell detachment from the \ncorrect extracellular matrix, thus disrupting integrin ligation. It is a \ncritical mechanism in preventing dysplastic cell growth or attachment to an \ninappropriate matrix. Anoikis prevents detached epithelial cells from colonizing \nelsewhere and is thus essential for tissue homeostasis and development. As \nanchorage-independent growth and epithelial-mesenchymal transition, two features \nassociated with anoikis resistance, are crucial steps during tumour progression \nand metastatic spreading of cancer cells, anoikis deregulation has now evoked \nparticular attention from the scientific community. The aim of this review is to \nanalyse the molecular mechanisms governing both anoikis and anoikis resistance, \nfocusing on their regulation in physiological processes, as well as in several \ndiseases, including metastatic cancers, cardiovascular diseases and diabetes.",
"Apoptosis has long been recognized as a critical mechanism of programmed cell \ndeath that is preserved among all eukaryotes and is involved in a variety of \ndisease processes. Malignant transformation of cells is associated with a \nconstellation of pro-survival mutations rendering them resistant to apoptosis. \nTraditional cancer therapy evokes cell death by inducing apoptosis; however, the \napoptotic resistance inherent in cancer cells has been a significant barrier to \neffective chemotherapy. More recently, other mechanisms of cell death have \nemerged as potential novel mechanisms for cancer therapies to induce cell death, \neither in addition to, or instead of, apoptosis-induced cytotoxic treatment. \nAutophagy is a process that occurs in all cells, but is induced in many types of \ncancer. Autophagy functions as both a cell survival and a cell death mechanism \ndepending on the context and the stimuli, which are likely exploitable for \ncancer therapy. Anoikis is also a physiologic process in normal cells used to \nmaintain homeostasis, in which cell death is induced in response to loss of \nextracellular membrane (ECM) attachment. Cancer cells are notoriously resistant \nto anoikis, enabling metastasis and new tumor growth beyond their original \nenvironment. Interestingly, autophagy may actually by a major contributor to \nanoikis resistance in cancer. As these two processes are elucidated in more \ndetail, there is great potential for novel targets that affect cancer cell \ndeath, in addition to the current cytotoxic agents.",
"Metastasis is a multistep process including dissociation of cancer cells from \nprimary sites, survival in the vascular system, and proliferation in distant \ntarget organs. As a barrier to metastasis, cells normally undergo an apoptotic \nprocess known as \"anoikis,\" a form of cell death due to loss of contact with the \nextracellular matrix or neighboring cells. Cancer cells acquire anoikis \nresistance to survive after detachment from the primary sites and travel through \nthe circulatory and lymphatic systems to disseminate throughout the body. \nBecause recent technological advances enable us to detect rare circulating tumor \ncells, which are anoikis resistant, currently, anoikis resistance becomes a hot \ntopic in cancer research. Detailed molecular and functional analyses of anoikis \nresistant cells may provide insight into the biology of cancer metastasis and \nidentify novel therapeutic targets for prevention of cancer dissemination. This \npaper comprehensively describes recent investigations of the molecular and \ncellular mechanisms underlying anoikis and anoikis resistance in relation to \nintrinsic and extrinsic death signaling, epithelial-mesenchymal transition, \ngrowth factor receptors, energy metabolism, reactive oxygen species, membrane \nmicrodomains, and lipid rafts.",
"As a barrier to metastasis of cancer, cells that lost contact with the \nneighbouring cells or extracellular matrix(Extracellular matrix, ECM) will be \nsubjected to apoptosis. This cell death process has been termed \"anoikis\". When \nnormal epithelial cells or solid tumor cells without metastatic potential detach \nfrom the primary site, and then enter into the circulatory system, the anoikis \nmechanism will be activated. The significance of anoikis is to prevent the \nshedding cells from growing and implanting into other inappropriate sites. Tumor \ncells, especially several malignant cells that is prone to transfer to distant \nsites, have properties of anti-anoikis, which facilitates metastasis as well as \ninvasion of tumor cells. The studies found that tumor cells can resist anoikis \nthrough multiple mechanisms: the pro-survival pathways are activated by cells \nautocrine growth factors and paracrine factors derived from neighboring cells; \ncells change the pattern of integrin expression so that they can receive \nsurvival signals from new environment; reactive oxygen species (ROS) activates \ngrowth factor receptors in a ligand-independent way to avoid apoptosis; and \nepithelial-mesenchymal transformation(EMT) is activated etc.. All of these \nmechanisms lead to activation of survival signals and inhibition of apoptotic \npathways, and ultimately cause resistance to anoikis as well as metastasis. This \npaper summarizes the key mechanisms of the current studies on metastasis, which \nalso suggest important targets for cancer therapy.",
"As a barrier to metastases, cells normally undergo apoptosis after they lose \ncontact with their extra cellular matrix or their neighbouring cells. This cell \ndeath process has been termed \"anoikis\". Tumour cells that acquire malignant \npotential have developed mechanisms to resist anoikis and thereby survive after \ndetachment from their primary site and while travelling through the lymphatic \nand circulatory systems. Defects in the death receptor pathway of caspase \nactivation, such as the over-expression of the caspase-8 inhibitor FLIP, can \nrender cells resistant to anoikis. Likewise, roadblocks in the mitochondrial \npathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, \ncan also confer resistance to anoikis. This review will focus on the roles of \nthe death receptor and mitochondrial pathways in anoikis and anoikis resistance \nand how targeting defects in these pathways can restore sensitivity to anoikis \nand serve as the basis for therapeutic adjuncts that prevent metastasis.",
"Detachment of adherent epithelial cells from the extracellular matrix induces \napoptosis, known as anoikis. Integrin stimulation protects cells from anoikis, \nbut the responsible mechanisms are not well known. Here, we demonstrated that a \npro-apoptotic GTP-binding protein, DAP3 (death-associated protein 3), is \ncritical for induction of anoikis. Down-regulation of DAP3 expression by \nantisense oligonucleotides inhibited anoikis. Conversely, overexpression of DAP3 \naugmented cell death and caspase activation induced by cell detachment. \nFurthermore, the association of DAP3 with FADD and the activation of caspase-8 \nwere induced by cell detachment. We also showed that DAP3 is phosphorylated by \nkinase Akt (PKB), and active Akt can nullify apoptosis induction by DAP3. \nMutation of a consensus Akt phosphorylation site in DAP3 renders it resistant to \nsuppression by active Akt in cells. Integrin ligation stimulates Akt activation \nand phosphorylation of DAP3 in intact cells, as well as suppresses the ability \nof DAP3 overexpression to augment anoikis. Involvement of DAP3 in anoikis \nsignaling demonstrates a novel role for this GTP-binding protein in apoptosis \ninduction caused by cell detachment.",
"Anoikis - apoptotic cell death triggered by loss of extracellular matrix (ECM) \ncontacts - is dysregulated in many chronic debilitating and fatal diseases. \nMechanisms rendering tumor cells resistant to anoikis, although not completely \nunderstood, possess significant therapeutic promise. In death receptor-mediated \nanoikis mechanisms, focal adhesion kinase (FAK) and receptor-interacting protein \n(RIP) dissociate, leading to association of RIP with Fas, formation of the \ndeath-inducing signaling complex (DISC), activation of caspase-3, and \npropagation of anoikis. In contrast, anoikis resistance is accomplished through \nconstitutive activation of survival pathways that include integrin-dependent \nactivation of FAK and extracellular-signal-regulated kinase (ERK). In addition, \nFAK and RIP association confers anoikis resistance by inhibiting the association \nof RIP with Fas and formation of the death signaling complex, which allows cells \nto escape anoikis. Up-regulation of CD44 also contributes to survival signals \nand promotes anoikis resistance. This review will focus on the roles of death \nreceptors, prosurvival pathways, and the molecular players involved in anoikis \nescalation and resistance in oral squamous cell carcinoma.",
"Epithelial cells require attachment to extracellular matrix (ECM) to suppress an \napoptotic cell death program termed anoikis. Here we describe a nonapoptotic \ncell death program in matrix-detached cells that is initiated by a previously \nunrecognized and unusual process involving the invasion of one cell into \nanother, leading to a transient state in which a live cell is contained within a \nneighboring host cell. Live internalized cells are either degraded by lysosomal \nenzymes or released. We term this cell internalization process entosis and \npresent evidence for entosis as a mechanism underlying the commonly observed \n\"cell-in-cell\" cytological feature in human cancers. Further we propose that \nentosis is driven by compaction force associated with adherens junction \nformation in the absence of integrin engagement and may represent an intrinsic \ntumor suppression mechanism for cells that are detached from ECM.",
"Apoptosis and proliferation are two dynamically and tightly regulated processes \nthat together maintain the homeostasis of renewable tissues. Anoikis is a \nsubtype of apoptosis induced by detachment of adherent cells from the \nextracellular matrix. By using the defined mTeSR1 medium and collecting freshly \ndetached cells, we found here that human pluripotent stem (PS) cells including \nembryonic stem (ES) cells and induced pluripotent stem cells are subject to \nconstant anoikis in culture, which is escalated in the absence of basic \nfibroblast growth factor (bFGF). Withdrawal of bFGF also promotes apoptosis and \ndifferentiation of the remaining adherent cells without affecting their cell \ncycle progression. Insulin-like growth factor 2 (IGF2) has previously been \nreported to act downstream of FGF signaling to support self-renewal of human ES \ncells. However, we found that IGF2 cannot substitute bFGF in the TeSR1-supported \nculture, although endogenous IGF signaling is required to sustain self-renewal \nof human ES cells. On the other hand, all of the bFGF withdrawal effects \nobserved here can be markedly prevented by the caspase inhibitor z-VAD-FMK. We \nfurther demonstrated that the bFGF-repressed anoikis is dependent on activation \nof ERK and AKT and associated with inhibition of Bcl-2-interacting mediator of \ncell death and the caspase-ROCK1-myosin signaling. Anoikis is independent of \npre-detachment apoptosis and differentiation of the cells. Because previous \nstudies of human PS cells have been focused on attached cells, our findings \nrevealed a neglected role of bFGF in sustaining self-renewal of human PS cells: \npreventing them from anoikis via inhibition of caspase activation.",
"Detachment from the extracellular matrix induces a form of programmed cell death \ntermed anoikis. Resistance to anoikis permits cancer cells to survive in \nsystemic circulation and facilitates their metastasis to distant organs. It is \nwell known that S100A4 is overexpressed in many tumors and involved in tumor \nmetastasis, but the mechanisms of the metastasis-promoting function of S100A4 \nare not fully understood. We hypothesized that S100A4 might play a role in \nanoikis of gastric cancer cells and further affects their metastasis. To test \nthis hypothesis, we changed the expression of S100A4 by means of RNA \ninterference or experimental overexpression and investigated the effect on \nanoikis. We found that knockdown of S100A4 by RNA interference led to \nsignificantly increased anoikis, whereas overexpression of S100A4 resulted in \ninhibition of anoikis. Furthermore, we provide evidence that inhibition of \nS100A4 resulted in the downregulation of α5 and αv integrin expression. These \nfindings suggest that S100A4 protects gastric cancer cells from anoikis by \nregulation of αv and α5 integrin expression, which sheds a novel light for the \nrole of S100A4 in cancer metastasis.",
"The extracellular matrix (ECM) plays a key role in cell-cell communication and \nsignaling, and the signals it propagates are important for tissue remodeling and \nsurvival. However, signals from disease-altered ECM may lead to \nanoikis-apoptotic cell death triggered by loss of ECM contacts. Previously, we \nfound that an altered fibronectin matrix triggers anoikis in human primary \nligament cells via a pathway that requires p53 transcriptional downregulation. \nHere we show that this p53 reduction is suppressed by transfecting cells with \nMdm2 antisense oligonucleotides or small interfering RNA. Similar results were \nfound in cells treated to prevent p53 and Mdm2 interactions. When p53 was \noverexpressed in cells lacking Mdm2 and p53, p53 levels were unaffected by \nanoikis conditions. However, cells cotransfected with p53 and wild type Mdm2, \nbut not a mutant Mdm2, exhibited decreased p53 levels in response to anoikis \nconditions. Thus, cells under anoikis conditions undergo p53 degradation that is \nmediated by Mdm2.",
"Detachment-induced cell death, or anoikis, is a type of apoptosis that occurs \nwhen epithelial cells lose their attachment to the extracellular matrix. Anoikis \nserves as a physiologic barrier to metastasis. Deviation from the tightly \nregulated mechanism of detachment-induced cell death might result in progression \nto metastatic cancer. Here, we investigated the function of CIIA in the \nregulation of anoikis. CIIA protein was upregulated in colon cancer tissue \nsamples. Knockdown of CIIA in metastatic colorectal carcinoma SW620 and KM12SM \ncells promoted detachment-induced cell death through the regulation of caspase \nactivation. Knockdown of CIIA also inhibited anchorage-independent growth in \nsoft agar and colony formation after suspension stress. These observations \nsuggest that CIIA is a novel negative regulator of anoikis.",
"Anoïkis is defined as programmed cell death induced by the loss of cell/matrix \ninteractions. Adhesion to structural glycoproteins of the extracellular matrix \nis necessary for survival of the differentiated adherent cells in the \ncardiovascular system, including endothelial cells, smooth muscle cells, \nfibroblasts, and cardiac myocytes. Adhesion is also a key factor for the \ndifferentiation of mesenchymal stem cells. In particular, fibronectin is \nconsidered a factor of survival and differentiation for many adherent cells. \nAdhesion generates cell tensional integrity (tensegrity) and repression of \napoptotic signals, whereas detachment has the opposite effect. Anoïkis plays a \nphysiological role by regulating cell homeostasis in tissues. However, anoïkis \ncan also be involved in pathological processes, as illustrated by the resistance \nto anoïkis in cancer and its enhancement in degenerative tissue remodeling. \nExtracellular mediators of anoïkis include matrix retraction, leading to loss of \ntensegrity in fibroblasts, pharmacological disengagement of integrins by \nRGD-like peptides and fragments of fibronectin, and focal adhesion disassembly \nby fragments of thrombospondin, plasminogen activator-1, and \nhigh-molecular-weight kininogen. In addition to binding of the RGD peptide by \nintegrins, the engagement of the heparin binding sites of adhesive glycoproteins \nwith glycosaminoglycans on the cell surface is also involved in the prevention \nof cell detachment-induced apoptosis. Proteases able to degrade adhesive \nglycoproteins, such as fibronectin, induce anoïkis of vascular adherent cells. \nActive proteases can either be secreted directly by inflammatory cells, as \nelastase and cathepsin G by polymorphonuclear leukocytes, chymase and tryptase \nby mast cells, and granzymes by lymphocytes, or generated from circulating \nzymogens by activation in close contact with the cells. This is the case for the \npericellular conversion of plasminogen to plasmin, which degrades fibronectin \nand induces anoïkis of smooth muscle cells. Involvement of proteases has also \nbeen proposed in the apoptotic response of cultured adherent cells to serum \nstarvation. Anoïkis is probably involved in pathological remodeling of \ncardiovascular tissues, including cardiac myocyte detachment in heart failure, \ndeendothelialization and plaque rupture in atherosclerosis, and smooth muscle \ncell disappearance in aneurysms and varicose veins. The absence of cell adhesion \nand growth resulting from cleavage of adhesive proteins also represents a major \nimpediment to cellular healing, including the absence of cell recolonization of \nproteolytically injured tissue and the low efficacy of cell transplantation. \nHowever, the exact role of anoïkis in cardiovascular pathologies remains to be \nfurther defined."
] | ['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:2000209', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0008219', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0016265', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0010941', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0043276'] |
56c8274f5795f9a73e00000d | [
24269728,
22900096,
24971881,
20846186,
25384799,
23197818,
22797053,
23114367
] | train | Which type of cells is affected in Amyotrophic Lateral Sclerosis? | factoid | Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neurons are affected. | Motor neurons | [
"Activation of microglia, CNS resident immune cells, is a pathological hallmark \nof amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting \nmotor neurons. Despite evidence that microglia contribute to disease \nprogression, the exact role of these cells in ALS pathology remains unknown. We \nimmunomagnetically isolated microglia from different CNS regions of SOD1(G93A) \nrats at three different points in disease progression: presymptomatic, symptom \nonset and end-stage. We observed no differences in microglial number or \nphenotype in presymptomatic rats compared to wild-type controls. Although after \ndisease onset there was no macrophage infiltration, there were significant \nincreases in microglial numbers in the spinal cord, but not cortex. At disease \nend-stage, microglia were characterized by high expression of galectin-3, \nosteopontin and VEGF, and concomitant downregulated expression of TNFα, IL-6, \nBDNF and arginase-1. Flow cytometry revealed the presence of at least two \nphenotypically distinct microglial populations in the spinal cord. \nImmunohistochemistry showed that galectin-3/osteopontin positive microglia were \nrestricted to the ventral horns of the spinal cord, regions with severe motor \nneuron degeneration. End-stage SOD1(G93A) microglia from the cortex, a less \naffected region, displayed similar gene expression profiles to microglia from \nwild-type rats, and displayed normal responses to systemic inflammation induced \nby LPS. On the other hand, end-stage SOD1(G93A) spinal microglia had blunted \nresponses to systemic LPS suggesting that in addition to their phenotypic \nchanges, they may also be functionally impaired. Thus, after disease onset, \nmicroglia acquired unique characteristics that do not conform to typical M1 \n(inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was \nobserved only in the most affected CNS regions, suggesting that overexpression \nof mutated hSOD1 is not sufficient to trigger these changes in microglia. These \nnovel observations suggest that microglial regional and phenotypic heterogeneity \nmay be an important consideration when designing new therapeutic strategies \ntargeting microglia and neuroinflammation in ALS.",
"Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease \ncaused by selective loss of motor neurons. In the ALS motor neurons, TAR \nDNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to \ncytoplasm and forms inclusions, suggesting that loss of a nuclear function of \nTDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism \ninclude regulation of transcription, mRNA stability, and alternative splicing of \npre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been \nelucidated. We sought to identify the molecular indicators reflecting on a \nTDP-43 function. Using exon array analysis, we observed a remarkable alteration \nof splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result \nof the depletion of TDP-43 expression in two types of cultured cells. In the \ncells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and \nPOLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 \nwas necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment \nof POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons \ncollected by laser capture microdissection with ALS. Our results suggest a loss \nof TDP-43 function in tissues affected with ALS, supporting the hypothesis that \na loss of function of TDP-43 underlies the pathogenesis of ALS.",
"Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial \namyotrophic lateral sclerosis (ALS), whereby the mutant proteins misfold and \naggregate to form intracellular inclusions. We report that both small \nubiquitin-like modifier (SUMO) 1 and SUMO2/3 modify ALS-linked SOD1 mutant \nproteins at lysine 75 in a motoneuronal cell line, the cell type affected in \nALS. In these cells, SUMO1 modification occurred on both lysine 75 and lysine 9 \nof SOD1, and modification of ALS-linked SOD1 mutant proteins by SUMO3, rather \nthan by SUMO1, significantly increased the stability of the proteins and \naccelerated intracellular aggregate formation. These findings suggest the \ncontribution of sumoylation, particularly by SUMO3, to the protein aggregation \nprocess underlying the pathogenesis of ALS.",
"Stem cell research raises hopes for incurable neurodegenerative diseases. In \namyotrophic lateral sclerosis (ALS), affecting the motoneurones of the central \nnervous system (CNS), stem cell-based therapy aims to replace dying host \nmotoneurones by transplantation of cells in disease-affected regions. Moreover, \ntransplanted stem cells can serve as a source of trophic factors providing \nneuroprotection, slowing down neuronal degeneration and disease progression.\nAIM: To determine the profile of seven trophic factors expressed by mesenchymal \nstem cells (MSC) and neural stem cells (NSC) upon stimulation with CNS protein \nextracts from SOD1-linked ALS rat model.\nMETHODS: Culture of rat MSC, NSC and fibroblasts were incubated with brain and \nspinal cord extracts from SOD1(G93A) transgenic rats and mRNA expression of \nseven growth factors was measured by quantitative PCR.\nRESULTS: MSC, NSC and fibroblasts exhibited different expression patterns. Nerve \ngrowth factor and brain-derived neurotropic factor were significantly \nupregulated in both NSC and MSC cultures upon stimulation with SOD1(G93A) CNS \nextracts. Fibroblast growth factor 2, insulin-like growth factor and \nglial-derived neurotropic factor were upregulated in NSC, while the same factors \nwere downregulated in MSC. Vascular endothelial growth factor A upregulation was \nrestricted to MSC and fibroblasts. Surprisingly, SOD1(G93A) spinal cord, but not \nthe brain extract, upregulated brain-derived neurotropic factor in MSC and \nglial-derived neurotropic factor in NSC.\nCONCLUSIONS: These results suggest that inherent characteristics of different \nstem cell populations define their healing potential and raise the concept of \nALS environment in stem cell transplantation.",
"Amyotrophic lateral sclerosis is the most common adult-onset motor neuron \ndisease and evidence from mice expressing amyotrophic lateral sclerosis-causing \nSOD1 mutations suggest that neurodegeneration is a non-cell autonomous process \nwhere microglial cells influence disease progression. However, \nmicroglial-derived neurotoxic factors still remain largely unidentified in \namyotrophic lateral sclerosis. With excitotoxicity being a major mechanism \nproposed to cause motor neuron death in amyotrophic lateral sclerosis, our \nhypothesis was that excessive glutamate release by activated microglia through \ntheir system [Formula: see text] (a cystine/glutamate antiporter with the \nspecific subunit xCT/Slc7a11) could contribute to neurodegeneration. Here we \nshow that xCT expression is enriched in microglia compared to total mouse spinal \ncord and absent from motor neurons. Activated microglia induced xCT expression \nand during disease, xCT levels were increased in both spinal cord and isolated \nmicroglia from mutant SOD1 amyotrophic lateral sclerosis mice. Expression of xCT \nwas also detectable in spinal cord post-mortem tissues of patients with \namyotrophic lateral sclerosis and correlated with increased inflammation. \nGenetic deletion of xCT in mice demonstrated that activated microglia released \nglutamate mainly through system [Formula: see text]. Interestingly, xCT deletion \nalso led to decreased production of specific microglial \npro-inflammatory/neurotoxic factors including nitric oxide, TNFa and IL6, \nwhereas expression of anti-inflammatory/neuroprotective markers such as \nYm1/Chil3 were increased, indicating that xCT regulates microglial functions. In \namyotrophic lateral sclerosis mice, xCT deletion surprisingly led to earlier \nsymptom onset but, importantly, this was followed by a significantly slowed \nprogressive disease phase, which resulted in more surviving motor neurons. These \nresults are consistent with a deleterious contribution of microglial-derived \nglutamate during symptomatic disease. Therefore, we show that system [Formula: \nsee text] participates in microglial reactivity and modulates amyotrophic \nlateral sclerosis motor neuron degeneration, revealing system [Formula: see \ntext] inactivation, as a potential approach to slow amyotrophic lateral \nsclerosis disease progression after onset of clinical symptoms.",
"The generation of amyotrophic lateral sclerosis (ALS) disease models is an \nimportant subject for investigating disease mechanisms and pharmaceutical \napplications. In transgenic mice, expression of a mutant form of superoxide \ndismutase 1 (SOD1) can lead to the development of ALS that closely mimics the \nfamilial type of ALS (FALS). Although SOD1 mutant mice show phenotypes similar \nto FALS, dissimilar drug responses and size differences limit their usefulness \nto study the disease mechanism(s) and identify potential therapeutic compounds. \nDevelopment of an in vitro model system for ALS is expected to help in obtaining \nnovel insights into disease mechanisms and discovery of therapeutics. We report \nthe establishment of an in vitro FALS model from human embryonic stem cells \noverexpressing either a wild-type (WT) or a mutant SOD1 (G93A) gene and the \nevaluation of the phenotypes and survival of the spinal motor neurons (sMNs), \nwhich are the neurons affected in ALS patients. The in vitro FALS model that we \ndeveloped mimics the in vivo human ALS disease in terms of the following: (a) \nselective degeneration of sMNs expressing the G93A SOD1 but not those expressing \nthe WT gene; (b) susceptibility of G93A SOD1-derived sMNs to form ubiquitinated \ninclusions; (c) astrocyte-derived factor(s) in the selective degeneration of \nG93A SOD1 sMNs; and (d) cell-autonomous, as well as non-cell-autonomous, \ndependent sMN degeneration. Thus, this model is expected to help unravel the \ndisease mechanisms involved in the development of FALS and also lead to \npotential drug discoveries based on the prevention of neurodegeneration.",
"BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset \nneurodegenerative disease characterized by ascending muscle weakness, atrophy \nand paralysis. Early muscle abnormalities that precede motor neuron loss in ALS \nmay destabilize neuromuscular junctions, and we have previously demonstrated \nalterations in myogenic regulatory factor (MRF) expression in vivo and in the \nactivation of myofiber-associated skeletal muscle satellite cells (SMSCs) in the \nmouse model of ALS (SOD1-G93A).\nMETHODS: To elucidate niche dependence versus cell-autonomous mutant SOD1 \n(mSOD1) toxicity in this model, we measured in vitro proliferation potential and \nMRF and cyclin gene expression in SMSC cultures derived from fast-twitch \nextensor digitorum longus and slow-twitch soleus muscles of SOD1-G93A mice.\nRESULTS: SMSCs from early presymptomatic (p40) to terminal, semi-paralytic \n(p120) SOD1-G93A mice demonstrated generally lower proliferation potential \ncompared with age-matched controls. However, induced proliferation was observed \nin surgically denervated wild-type animals and SOD1-G93A animals at p90, when \ncritical denervation arises. SMSCs from fast and slow muscles were similarly \naffected by mSOD1 expression. Lowered proliferation rate was generally \ncorroborated with decreased relative MRF expression levels, although this was \nmost prominent in early age and was modulated by muscle type origin. Cyclins \ncontrolling cell proliferation did not show modifications in their mRNA levels; \nhowever, the expression of cyclin-dependent kinase inhibitor 1A (Cdkn1a), which \nis known to promote myoblast differentiation, was decreased in SOD1-G93A \ncultures.\nCONCLUSIONS: Our data suggest that the function of SMSCs is impaired in \nSOD1-G93A satellite cells from the earliest stages of the disease when no \ncritical motor neuron loss has been described.",
"Spasticity is a common and disabling symptom observed in patients with central \nnervous system diseases, including amyotrophic lateral sclerosis, a disease \naffecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, \nspasticity is traditionally thought to be the result of degeneration of the \nupper motor neurons in the cerebral cortex, although degeneration of other \nneuronal types, in particular serotonergic neurons, might also represent a cause \nof spasticity. We performed a pathology study in seven patients with amyotrophic \nlateral sclerosis and six control subjects and observed that central \nserotonergic neurons suffer from a degenerative process with prominent neuritic \ndegeneration, and sometimes loss of cell bodies in patients with amyotrophic \nlateral sclerosis. Moreover, distal serotonergic projections to spinal cord \nmotor neurons and hippocampus systematically degenerated in patients with \namyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of \namyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and \nspinal cord before onset of motor symptoms. Furthermore, there was noticeable \natrophy of serotonin neuronal cell bodies along with neuritic degeneration at \ndisease onset. We hypothesized that degeneration of serotonergic neurons could \nunderlie spasticity in amyotrophic lateral sclerosis and investigated this \nhypothesis in vivo using tail muscle spastic-like contractions in response to \nmechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail \nmuscle spastic-like contractions were observed at end-stage. Importantly, they \nwere abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line \nwith this, 5-hydroxytryptamine-2b receptor expression was strongly increased at \ndisease onset. In all, we show that serotonergic neurons degenerate during \namyotrophic lateral sclerosis, and that this might underlie spasticity in mice. \nFurther research is needed to determine whether inverse agonists of \n5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity \nin patients with amyotrophic lateral sclerosis."
] | nan |
5e36cf8eb5b409ea53000007 | [
29899448
] | train | Which type of cells protect Haematopoietic stem and progenitor cells (HSPCs) from ultraviolet-light-induced DNA damage in aquatic vertebrates? | factoid | Haematopoietic stem and progenitor cells (HSPCs) require a specific microenvironment to grow and are protected from ultraviolet-light-induced DNA damages by melanocytes. Mutations that lack melanocytes have normal steady-state haem atopoiesis under standard laboratory conditions while melanocytes above the stem cell niche protect HSPCs against ultraviolet- light-induced damage. | melanocytes | [
"Author information:\n(1)Department of Stem Cell and Regenerative Biology and Harvard Stem Cell \nInstitute, Harvard University, Cambridge, MA, USA.\n(2)Stem Cell Program and Division of Hematology/Oncology, Boston Children's \nHospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, \nHarvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.\n(3)Department of Pediatric Hematology and Oncology, Center for Pediatrics, \nMedical Center-University of Freiburg, Faculty of Medicine, University of \nFreiburg, Freiburg, Germany.\n(4)Division of Hematology, Department of Medicine, Brigham and Women's Hospital, \nHarvard Medical School, Boston, MA, USA.\n(5)US Fish and Wildlife Service, Private John Allen National Fish Hatchery, \nTupelo, MS, USA.\n(6)Department of Biology, Stanford University, Stanford, CA, USA.\n(7)US Geological Survey, Great Lakes Science Center, Hammond Bay Biological \nStation, Millersburg, MI, USA.\n(8)Molecular Cell Biology, University of California, Merced, CA, USA.\n(9)Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard \nMedical School, Charlestown, MA, USA.\n(10)Department of Dermatology, Medical Center-University of Freiburg, Faculty of \nMedicine, University of Freiburg, Freiburg, Germany.\n(11)Department of Cellular and Molecular Immunology, Max Planck Institute of \nImmunobiology and Epigenetics, Freiburg, Germany.\n(12)Developmental Biology, Faculty of Biology, Centre for Biological Signalling \nStudies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany.\n(13)Department of Stem Cell and Regenerative Biology and Harvard Stem Cell \nInstitute, Harvard University, Cambridge, MA, USA. zon@enders.tch.harvard.edu.\n(14)Stem Cell Program and Division of Hematology/Oncology, Boston Children's \nHospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, \nHarvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA. \nzon@enders.tch.harvard.edu."
] | nan |
5e52be146d0a27794100004a | [
30286710
] | train | Which type of distance is used in the R-package XenofilteR? | factoid | The R-package XenofilteR separates mouse from human sequence reads based on the edit-distance between a sequence read and reference genome. | Edit-distance | [
"BACKGROUND: Mouse xenografts from (patient-derived) tumors (PDX) or tumor cell \nlines are widely used as models to study various biological and preclinical \naspects of cancer. However, analyses of their RNA and DNA profiles are \nchallenging, because they comprise reads not only from the grafted human cancer \nbut also from the murine host. The reads of murine origin result in false \npositives in mutation analysis of DNA samples and obscure gene expression levels \nwhen sequencing RNA. However, currently available algorithms are limited and \nimprovements in accuracy and ease of use are necessary.\nRESULTS: We developed the R-package XenofilteR, which separates mouse from human \nsequence reads based on the edit-distance between a sequence read and reference \ngenome. To assess the accuracy of XenofilteR, we generated sequence data by in \nsilico mixing of mouse and human DNA sequence data. These analyses revealed that \nXenofilteR removes > 99.9% of sequence reads of mouse origin while retaining \nhuman sequences. This allowed for mutation analysis of xenograft samples with \naccurate variant allele frequencies, and retrieved all non-synonymous somatic \ntumor mutations.\nCONCLUSIONS: XenofilteR accurately dissects RNA and DNA sequences from mouse and \nhuman origin, thereby outperforming currently available tools. XenofilteR is \nopen source and available at https://github.com/PeeperLab/XenofilteR ."
] | nan |
56fcf1b8cf1c325851000005 | [
16034473,
15371550,
21841785
] | train | Which type of genes are modulated by SATB1? | factoid | Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. At an Associative t-test threshold of P | it supresses cell cytokines and differentiation genes | [
"Gene expression changes in CD4 + Vbeta8+ T cells energized by in vivo exposure \nto staphylococcal enterotoxin B (SEB) bacterial superantigen compared to CD4 + \nVbeta8+ non-energic T cells were assessed using DNA microarrays containing 5184 \nmurine complementary DNAs. Anergy in splenic T cells of SEB-immunized BALB/c \nmice was verified by dramatically reduced proliferative capacity and an 8 x \noverexpression of GRAIL mRNA in CD4 + Vbeta8+ T cells taken from mice 7 days \nafter injection. At an Associative t-test threshold of P<0.0005, 96 genes were \noverexpressed or detected only in anergic T cells, while 256 genes were \nsuppressed or not detected in anergic T cells. Six of eight differential \nexpressions tested using real-time quantitative PCR were validated. Message for \nB-Raf was detected only in non-anergic cells, while expression of the TCR \nsignaling modulator Slap (Src-like adapter protein) and the TCR zeta-chain \nspecific phosphatase Ptpn3 was enhanced. Modulation of multiple genes suggests \ndownregulation of Wnt/beta-catenin signaling and enhanced Notch signaling in the \nanergic cells. Consistent with previous reports in a non-superantigen in vivo \nanergy model, mRNA for CD18 and the transcription factor Satb1 (special \nAT-rich-binding protein 1) was increased in SEB-energized T cells. This is the \nfirst report of global transcriptional changes in CD4+ T cells made anergic by \nsuperantigen exposure.",
"Chromatin modulation at various cis-acting elements is critical for V(D)J \nrecombination during T and B cell development. MARbeta, a matrix-associated \nregion (MAR) located upstream of the T cell receptor beta (TCRbeta) enhancer \n(Ebeta), serves a crucial role in silencing Ebeta-mediated TCR activation. By \nDNaseI hypersensitivity assays, we show here that overexpression of the MAR \nbinding proteins SMAR1 and Cux/CDP modulate the chromatin structure at MARbeta. \nWe further demonstrate that the silencer function of MARbeta is mediated \nindependently by SMAR1 and Cux/CDP as judged by their ability to repress \nEbeta-dependent reporter gene expression. Moreover, the repressor activity of \nSMAR1 is strongly enhanced in the presence of Cux/CDP. These two proteins \nphysically interact with each other and colocalize within the perinuclear region \nthrough a SMAR1 domain required for repression. The repression domain of SMAR1 \nis separate from the MARbeta binding domain and contains a nuclear localization \nsignal and an arginine-serine (RS)-rich domain, characteristic of pre-mRNA \nsplicing regulators. Our data suggest that at the double positive stage of T \ncell development, cis-acting MARbeta elements recruit the strong negative \nregulators Cux and SMAR1 to control Ebeta-mediated recombination and \ntranscription.",
"Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune \nhomeostasis. Lack of effector T cell (T(eff) cell) function and gain of \nsuppressive activity by T(reg) cells are dependent on the transcriptional \nprogram induced by Foxp3. Here we report that repression of SATB1, a genome \norganizer that regulates chromatin structure and gene expression, was crucial \nfor the phenotype and function of T(reg) cells. Foxp3, acting as a \ntranscriptional repressor, directly suppressed the SATB1 locus and indirectly \nsuppressed it through the induction of microRNAs that bound the SATB1 3' \nuntranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells \ncaused loss of suppressive function, establishment of transcriptional T(eff) \ncell programs and induction of T(eff) cell cytokines. Our data support the \nproposal that inhibition of SATB1-mediated modulation of global chromatin \nremodeling is pivotal for maintaining T(reg) cell functionality."
] | ['http://www.uniprot.org/uniprot/SATB1_HUMAN', 'http://www.uniprot.org/uniprot/SATB1_MOUSE'] |
530cf4fe960c95ad0c00000b | [
23664448,
22452896,
24086949,
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18520300,
22071596,
21554040,
23683257
] | train | Which type of lung cancer is afatinib used for? | factoid | Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. Trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib. | EGFR-mutant non small cell lung carcinoma or EGFR-mutant NSCLC | [
"Reversible ATP-competitive inhibitors targeting the epidermal growth factor \nreceptor (EGFR) have been established as the most effective treatment of \npatients with advanced non-small cell lung cancer (NSCLC) harboring \"activating\" \nmutations in exons 19 and 21 of the EGFR gene. However, clinical activity is \nlimited by acquired resistance which on average develops within 10 months of \ncontinued treatment. The mechanisms for acquired resistance include selection of \nthe EGFR T790M mutation in approximately 50% of cases, and MET gene \namplification, PIK3CA gene mutation, transdifferentiation into small-cell lung \ncancer and additional rare or unkown mechanisms. Afatinib is a small molecule \ncovalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine \nkinases. In preclinical studies, afatinib not only inhibited the growth of \nmodels with common activating EGFR mutations, but was also active in lung cancer \nmodels harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical \nefficacy of afatinib has been extensively studied in the LUX-Lung study program. \nThese trials showed promising efficacy in patients with EGFR-mutant NSCLC or \nenriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or \nerlotinib. Here we review the current status of clinical application of afatinib \nin NSCLC. We also discuss clinical aspects of resistance to afatinib and \nstrategies for its circumvention.",
"BACKGROUND: Afatinib, an irreversible ErbB-family blocker, has shown preclinical \nactivity when tested in EGFR mutant models with mutations that confer resistance \nto EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients \nwith advanced lung adenocarcinoma with previous treatment failure on EGFR \ntyrosine-kinase inhibitors.\nMETHODS: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV \nadenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) \nperformance score of 0-2 who had received one or two previous chemotherapy \nregimens and had disease progression after at least 12 weeks of treatment with \nerlotinib or gefitinib. We used a computer-generated sequence to randomly \nallocate patients (2:1) to either afatinib (50 mg per day) or placebo; all \npatients received best supportive care. Randomisation was done in blocks of \nthree and was stratified by sex and baseline ECOG performance status (0-1 vs 2). \nInvestigators, patients, and the trial sponsor were masked to treatment \nassignment. The primary endpoint was overall survival (from date of \nrandomisation to death), analysed on an intention-to-treat basis. This study is \nregistered with ClinicalTrials.gov, number NCT00656136.\nFINDINGS: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, \n585 of whom were randomly allocated to treatment (390 to afatinib, 195 to \nplacebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the \nafatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio \n1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in \nthe afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo \ngroup (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No \ncomplete responses to treatment were noted; 29 (7%) patients had a partial \nresponse in the afatinib group, as did one patient in the placebo group. \nSubsequent cancer treatment was given to 257 (68%) patients in the afatinib \ngroup and 153 (79%) patients in the placebo group. The most common adverse \nevents in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] \nwere grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). \nThese events occurred less often in the placebo group (18 [9%] of 195 patients \nhad diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related \nserious adverse events occurred in 39 (10%) patients in the afatinib group and \none (<1%) patient in the placebo group. We recorded two possibly \ntreatment-related deaths in the afatinib group.\nINTERPRETATION: Although we recorded no benefit in terms of overall survival \nwith afatinib (which might have been affected by cancer treatments given after \nprogression in both groups), our findings for progression-free survival and \nresponse to treatment suggest that afatinib could be of some benefit to patients \nwith advanced lung adenocarcinoma who have failed at least 12 weeks of previous \nEGFR tyrosine-kinase inhibitor treatment.\nFUNDING: Boehringer Ingelheim Inc.",
"Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are \nvaluable treatments for EGFR-mutated non-small cell lung cancer (NSCLC). \nAnti-EGFR antibodies are widely used in the treatment of head and neck squamous \ncell carcinomas (HNSCC) and in KRAS wild-type colorectal cancer. The \nfirst-generation, reversible EGFR inhibitors erlotinib and gefitinib in the \nfirst-line setting provide superior progression-free survival and quality of \nlife compared to conventional chemotherapy in NSCLC harboring activating EGFR \nmutations. However, these therapies eventually fail and new options are needed. \nAfatinib is a novel irreversible inhibitor of the ErbB family members EGFR, \ntyrosine kinase-type cell surface receptors HER2 and HER4. It shows preclinical \nefficacy in NSCLC with common EGFR-activating mutations and the T790M mutation \ntypically associated with EGFR TKI resistance. Preclinical activity is seen in \nother tumor types as well, including HNSCC. Clinically, afatinib has been \nevaluated in the broad-reaching LUX Lung trial program, with significant \nactivity seen in the first and later-line settings. It is also under \ninvestigation in multiple other tumor types. This review will stress on \nafatinib's preclinical pharmacology, pharmacokinetics and clinical activity with \na focus on NSCLC.",
"Genetic alterations in the kinase domain of the epidermal growth factor receptor \n(EGFR) in non-small cell lung cancer (NSCLC) patients are associated with \nsensitivity to treatment with small molecule tyrosine kinase inhibitors. \nAlthough first-generation reversible, ATP-competitive inhibitors showed \nencouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR \nmutations, almost all patients developed resistance to these inhibitors over \ntime. Such resistance to first-generation EGFR inhibitors was frequently linked \nto an acquired T790M point mutation in the kinase domain of EGFR, or \nupregulation of signaling pathways downstream of HER3. Overcoming these \nmechanisms of resistance, as well as primary resistance to reversible EGFR \ninhibitors driven by a subset of EGFR mutations, will be necessary for \ndevelopment of an effective targeted therapy regimen. Here, we show that \nBIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, \npotently suppresses the kinase activity of wild-type and activated EGFR and HER2 \nmutants, including erlotinib-resistant isoforms. Consistent with this activity, \nBIBW2992 suppresses transformation in isogenic cell-based assays, inhibits \nsurvival of cancer cell lines and induces tumor regression in xenograft and \ntransgenic lung cancer models, with superior activity over erlotinib. These \nfindings encourage further testing of BIBW2992 in lung cancer patients harboring \nEGFR or HER2 oncogenes.",
"Approximately 10 to 15% of patients with non-small cell lung cancer have tumors \nthat depend on activation of the epidermal growth factor receptor (EGFR), as \nevidenced by mutations in EGFR. In these patients, there is often an initial \ndramatic response to treatment with the first-generation EGFR tyrosine kinase \ninhibitors (TKIs) erlotinib or gefitinib. A small number of patients with EGFR \nmutations have primary resistance to erlotinib and gefitinib, and most patients \nwho initially respond to treatment with erlotinib or gefitinib will develop \nresistance to first-generation EGFR TKIs. The problems with both primary and \nacquired resistance to erlotinib and gefitinib support the need for development \nof additional agents that inhibit EGFR signaling in such patients. This is an \noverview of three representative second-generation EGFR TKIs. HKI-272, a \nsecond-generation irreversible EGFR TKI that also inhibits HER2, has completed \naccrual of a phase II trial in both untreated patients and patients with \nacquired resistance to erlotinib or gefitinib. XL647 is a reversible inhibitor \nof EGFR, HER2, and vascular epidermal growth factor receptor. Preclinical work \nshows that XL647 can inhibit cell lines bearing mutated forms of EGFR that have \nbeen associated with acquired resistance. BIBW2992 is an irreversible EGFR TKI \nthat also inhibits HER2 and vascular epidermal growth factor receptors. In vitro \nwork shows that this compound inhibits wild-type EGFR, EGFR exon 19 deletion, \nEGFR L858R, and EGFR T790M, the mutation associated with acquired resistance. \nThe preliminary results from phase I and phase II trials for BIBW-2992 and XL647 \nare discussed.",
"PURPOSE: This Phase I study determined the maximum-tolerated dose (MTD) of \nafatinib (Afatinib is an investigational compound and its safety and efficacy \nhave not yet been established) (BIBW 2992; trade name not yet approved by FDA), \nan irreversible inhibitor of epidermal growth factor receptor (EGFR)/human \nepidermal growth factor receptor (HER)1 and 2, up to a dose of 50 mg/day in \nadvanced non-small cell lung cancer (NSCLC), to establish the recommended dose \nfor Phase II.\nMETHODS: Patients with advanced NSCLC who had received prior platinum-doublet \nchemotherapy and/or erlotinib/gefitinib therapy, or who were ineligible for, or \nnot amenable to, treatment with established therapies, received oral afatinib \nonce daily. The MTD was determined based on dose-limiting toxicities (DLTs); \nother assessments included safety, pharmacokinetic profile, antitumour activity \naccording to response evaluation criteria in solid tumours and EGFR/HER1 \nmutation analysis where possible.\nRESULTS: Twelve evaluable patients were treated at doses of 20-50 mg/day. One \nDLT was observed at 50 mg/day in Course 1 (Grade 3 mucositis). The most frequent \ndrug-related adverse events were diarrhoea, dry skin, stomatitis, rash, \nparonychia and anorexia; most were Grade 1 or 2. Six out of 12 patients had \ntumour size reductions; durable stable disease was achieved in three patients \nincluding one with EGFR/HER1 exon 19 and T790 M mutations. Peak plasma \nconcentrations of afatinib were reached 3-4 h after administration and declined \nwith a half-life of 30-40 h. Afatinib 50 mg/day was well tolerated with an \nacceptable safety profile during Phase I.\nCONCLUSION: Recommended dose for Phase II was defined as 50 mg/day for Japanese \npatients; the same as for non-Japanese patients.",
"Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer \n(NSCLC) represents a distinct disease entity whose molecular phenotype predicts \nexquisite sensitivity to the reversible EGFR-tyrosine kinase inhibitors (TKIs) \ngefitinib or erlotinib. However, primary or acquired resistance to these agents \nremains a major clinical problem. Afatinib is a novel dual irreversible \nEGFR/HER2 TKI that has been shown in preclinical studies to potentially prevent, \ndelay or overcome resistance to reversible EGFR-TKIs. On this basis, the \nLUX-Lung clinical trial program has been recently launched for testing this \nmolecule in advanced NSCLC patients. Notably, early results from the randomized \nLUX-Lung 1 trial indicate that afatinib significantly prolongs progression-free \nsurvival compared with placebo in pretreated patients with clinically acquired \nresistance to gefitinib or erlotinib. On the other hand, the LUX-Lung 2 trial \nshows that afatinib is highly active in the EGFR-mutant subgroup of patients. \nWhile these preliminary data open a new exciting scenario for the future \ndevelopment of anti-EGFR therapies in NSCLC, ongoing afatinib trials will \ndefinitively establish a role for this molecule in the treatment of advanced \nNSCLC.",
"Lung cancer is the leading cause of cancer-related death in the world. Prior to \nthe era of targeted therapy, platinum-based doublet chemotherapy was the \nfirst-line therapy of choice for patients with metastatic non-small-cell lung \ncancer (NSCLC). The availability of agents that target epidermal growth factor \nreceptor (EGFR)-tyrosine kinase, as well as inhibitors against anaplastic \nlymphoma kinase (ALK) gene rearrangement or ROS-1 gene rearrangement product, \nhas provided promising clinical benefits in specific subpopulations of NSCLC. At \npresent, only first-generation EGFR-tyrosine kinase inhibitors (TKIs) (erlotinib \nand gefitinib) are available for clinical use. Second-generation irreversible \nEGFR-TKIs, such as afatinib, are still in clinical trials. In current clinical \npractice, EGFR-TKI is the first-line treatment of choice for metastatic NSCLC \npatients with tumor EGFR mutation or as salvage therapy in NSCLC patients who \nreceived systemic chemotherapy previously. Platinum-based doublet chemotherapy \ncontinues to be the standard of care for those treatment-naïve patients with \nEGFR wild -type tumor or unknown EGFR status. Even though all investigators \nagree with the use of EGFR-TKI as the first-line treatment in tumor EGFR-mutated \npatients, only 10-30% of NSCLC patients have mutated EGFR, and there was no \nobvious survival difference when EGFR-TKIs were used in a second-line setting \nversus a first-line treatment in EGFR-mutated patients. Thus, the molecular \ncomplexity of lung cancer emphasizes the need for optimizing treatment by \nseeking a more personalized approach to care, including searching for driver \noncogenes, managing the emergence of resistance and overcoming that resistance, \nand optimizing the sequence of treatment. Numerous other novel targeted agents \nare now in clinical development, including new agents targeting novel pathways \nand those that may have the potential to overcome the limitations or resistance \nassociated with currently available EGFR-TKIs. In this report, we review the \nclinical data of EGFR-TKIs as molecular-targeted therapies in NSCLC."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009369', 'http://www.disease-ontology.org/api/metadata/DOID:3683', 'http://www.disease-ontology.org/api/metadata/DOID:7696', 'http://www.disease-ontology.org/api/metadata/DOID:3908', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008175', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008171', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008168', 'http://www.disease-ontology.org/api/metadata/DOID:1324'] |
5147c088d24251bc05000026 | [
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] | train | Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome? | factoid | Small-cell lung cancer is most commonly associated with Lambert-Eaton syndrome. Case reports suggest that other non-small-cell lung cancer types, such as large-cell neuroendocrine carcinoma and squamous cell carcinoma, can be also very rarely associated this syndrome. | small-cell lung cancer | [
"BACKGROUND: To enhance the acknowledgement of Lambert-Eaton syndrome in patients \nwith small cell lung cancer.\nMETHODS: Retrospective case analysis of Lambert-Eaton syndrome in patients with \nsmall cell lung cancer in our hospital.\nRESULTS: The characteristics of electromyography for Lambert-Eaton syndrome was \nreduction in action potential amplitude after repetitive peripheral nerve \nstimulation at low frequency and increased amplitude at high frequency.There \nwere 10 cases of Lambert-Eaton syndrome in 332 pathologically diagnosed small \ncell lung cancer,9 male and 1 female with an average age of 57.6±4.9.Nine of 10 \ncases were among 50 to 69.All patients except one experienced myasthenia,mainly \nin lower extremities,2 to 36 months (median:6 months) before the diagnosis of \nsmall cell lung cancer.Treatment of small cell lung cancer may improve the \nsymptoms of Lambert-Eaton syndrome.\nCONCLUSIONS: Improving the recognition of Lambert-Eaton syndrome may be helpful \nto identify early small cell lung cancer and improve the prognosis,as the \nsymptom of muscular weakness usually appears early before the diagnosis of small \ncell lung cancer.",
"We report the case of a 50-year-old man with paraneoplastic cerebellar \ndegeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS) associated with \nprimary double lung cancer. He developed acute progressive double vision, \nslurred speech, and gait disturbance. Neurological examination revealed \ndiplopia, mild ptosis, bilateral horizontal gaze-evoked nystagmus, and \ncerebellar limb and truncal ataxia. The diffusion image of brain magnetic \nresonance imaging (MRI) revealed no abnormal findings in the cerebellum. On the \nbasis of the diagnosis of acute cerebelitis, he was given methylprednisolone \npulse therapy followed by oral prednisolone, which gradually improved his \nneurological signs and symptoms. The analysis of the possible etiology suggested \nthat the PCD was induced by lung cancer, which led to ataxia. A chest computed \ntomography scan revealed mass lesions of irregular shape and unclear margins in \nthe upper lobe of the right lung and a small nodule tumor in the upper lobe of \nthe left lung. We performed transbronchial needle aspiration and detected the \nbronchioloalveolar carcinoma of the right lung. An electromyogram showed waxing \nphenomenon in the ulnar nerve at high-frequency (50Hz) stimulation. The serum \nlevels of anti-P/Q-type voltage-gated calcium channel (VGCC) antibody were \nelavated in the patient. These findings confirmed that the pathogenesis of the \ncondition of this patient to be associated with LEMS. His cerebellar symptoms \nwere considered to be caused by the PCD, and the diplopia, ptosis, and \nhyporeflexia were attributed to LEMS. We performed upper left lobectomy with \nmediastinal lymphnode dissection via video-assisted thoracoscopic surgery. A \nhistological study detected small cell carcinoma. A diagnosis of double primary \nlung cancer was made. Physicians need to be aware that patients may develop PCD \nand LEMS associated with anti-VGCC antibody caused by small cell lung cancer, \nand a mass survey should be conducted and careful examinations performed.",
"Paraneoplastic cerebellar degeneration may occur in association with \nLambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the \nco-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not \nbeen previously reported. A 67-year-old woman presented with a complex partial \nseizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' \nsigns, all of which improved spontaneously within 6 weeks. Approximately 8 weeks \nafter symptom onset, the patient became encephalopathic, she had a further \ncomplex partial seizure, and she became areflexic with potentiation of deep \ntendon reflexes. Radiological, bronchoscopic and histological investigations \nrevealed small-cell lung cancer, and neurophysiological investigations confirmed \na diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel \nantibodies were identified in the serum, which increased as the signs of \nopsoclonus and myoclonus resolved. The encephalopathy and clinical features of \nLEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous \nimprovement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this \nsyndrome may occur in association with LEMS. Antivoltage-gated calcium-channel \nantibodies are not implicated in the pathogenesis of paraneoplastic \nopsoclonus-myoclonus syndrome.",
"BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic \nsyndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in \nLEMS patients without a SCLC. We studied how this clinical information, which is \nreadily available at the first consultation, can be used to predict the presence \nof SCLC.\nPATIENTS AND METHODS: In our study we included 52 LEMS patients with SCLC and 45 \nnon-tumor patients (NT-LEMS). We interviewed patients using a structured \nchecklist and reviewed their clinical records. We compared frequency and onset \nof symptoms during the course of LEMS.\nRESULTS: In the first six months, over half the SCLC-LEMS patients had developed \nseven separate symptoms, while NT-LEMS patients developed only two symptoms. \nProximal leg weakness and dry mouth were early symptoms in both groups. Rapid \ninvolvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037), \ndistal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile \ndysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients \nin both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, \nwere almost exclusively related to SCLC-LEMS.\nCONCLUSION: A rapidly progressive course of disease from onset in LEMS patients \nshould raise a high suspicion of SCLC. Special attention should be paid to \ninvolvement of upper extremities, involvement of distal arm and distal leg \nmuscles, to erectile dysfunction and probably ataxia in order to discriminate \nbetween SCLC-LEMS and NT-LEMS.",
"Brain FDG-PET after radiation therapy is classically used to differentiate \nbetween tumor recurrence and radiation-related tumor necrosis. Little is known \nabout FDG-PET in patients with radiation-induced leukoencephalopathy without \nradiological aspect of necrosis. We present a 69-year-old woman who had \npreventive whole brain radiation after a diagnosis of paraneoplastic \nLambert-Eaton syndrome related to small cell lung cancer Five months after \nradiation therapy, she developed radiation-induced leukoencephalopathy \nmanifested by ataxia. Profound cerebellar hypometabolism on FDG-PET was in \ncontrast with the presence of only discrete cerebellar white matter changes on \nMRI. FDG-PET abnormalities seem to correlate better with clinical signs related \nto radiation-associated brain toxicity than MRI.",
"INTRODUCTION: The diagnosis and treatment of the neurological paraneoplastic \nsyndromes associated with lung cancer can pose a challenge both to general \nphysicians and neurologists as well as pulmonologists.\nCASE REPORT: A 53 year-old heavy smoker presented with a Lambert-Eaton \nmyasthenic syndrome (LEMS). Bronchoscopy was normal but radiological \nexaminations revealed a lymph node in site 4R. The pathological diagnosis after \nmediastinoscopy was negative. Twenty-five months later, an opacity on chest \nX-ray led to a biopsy which revealed a squamous cell carcinoma. A lobectomy was \nperformed for a pT2N0M0 lesion. A significant improvement of neurological \nsymptoms was seen. The myasthenic syndrome reappeared 21 months later. A local \nand general relapse was diagnosed. The patient died 10 months later despite \nchemotherapy.\nCONCLUSION: LEMS occurs because of an immunological reaction against \nvoltage-dependent calcium channels. LEMS is generally associated with small cell \nlung cancer occurring in three percent of cases. However, the case that we \nreport shows the unusual association of LEMS with non small-cell lung cancer and \nhighlights the difficulties associated in the management of this condition.",
"The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which \nautoantibodies are directed against voltage-gated calcium channels (VGCCs) at \npresynaptic nerve terminals. We first demonstrated the presence of P/Q-type and \nN-type VGCCs in digitonin extracts prepared from human and rabbit cerebellum \nusing the specific ligands 125I-omega-conotoxin MVIIC (125I-omega-CmTx) and \n125I-omega-conotoxin GVIA (125I-omega-CgTx), respectively. We then tested sera \nfrom 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 \nhealthy or other neurological, SCLC or autoimmune disease controls in an \nimmunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in \nhuman cerebellar extract. Sixty-six of 72 LEMS serum samples (91.7%) were \npositive for the presence of VGCC antibodies, as defined as a titre greater than \n3 standard deviations above the mean for the healthy controls (n = 22). Rabbit \ncerebellar extract as antigen gave similar results (r = 0.94, P < 0.001, n = \n30). By contrast, only 24/72 (33%) LEMS sera were positive in the assay for \nanti-N-type VGCC antibodies using 125I-omega-CgTx. All these 24 were also \npositive in the 125I-omega-CmTx assay. All healthy and disease control sera were \nnegative in both assays. The anti-P/Q-type VGCC antibody titres did not \ncorrelate with an electrophysiological index of disease severity across \nindividuals; however, longitudinal studies in a LEMS patient with SCLC receiving \nchemotherapy, and in a non-SCLC LEMS patient receiving immunosuppressive therapy \nshowed an inverse relation between antibody titre and disease severity. These \nresults support the view that anti-P/Q-type VGCC antibodies are implicated in \nthe motor disorder in LEMS, and show that the omega-CmTx radioimmunoassay is a \nhighly specific and sensitive means of detecting them.",
"Lambert-Eaton myasthenic syndrome (LEMS) is a rare type of neuromusculer \nconduction disorder. This disease can be seen with lung cancer and, it is \nassociated with otoimmunity. Among the symptoms of lung cancer LEMS can be seen, \nbut it is very rare. In this case, LEMS symptoms were analyzed before lung \ncancer symptoms. The localization of the tumor was near the pulmonary artery. By \nthe early diagnose, the patient had the chance of cure.",
"Lambert-Eaton myasthenic syndrome (LEMS) developed in a patient with presumed \nchronic inflammatory demyelinating polyneuropathy (CIDP) and negative chest CT. \nSince antibodies against both Hu and voltage-gated calcium channel (VGCC) were \ndetected, repeated chest CT was performed, which eventually showed a pulmonary \nmass lesion. Biopsy revealed small cell lung cancer (SCLC) indicating the \nimportance of repeated chest CT in LEMS even when an existing autoimmune-like \ndisease and negative CT may suggest an autoimmune origin. This is the first \nreport of paraneoplastic CIDP and LEMS associated with anti-Hu, anti-VGCC and \nSCLC.",
"We studied whether a difference exists in the development of symptoms of the \nLambert-Eaton myasthenic syndrome (LEMS) between patients with or without small \ncell lung cancer (SCLC). We assessed symptoms in 38 LEMS patients, 13 with SCLC, \nby interviewing them using a structured checklist, backed up by a review of \ntheir clinical records, and compared the frequency and time scale of symptoms \nduring the course of LEMS. Bulbar (87%) and autonomic (95%) symptoms for the \nwhole group were more common than reported in the literature. Frequencies of \nsymptoms did not differ significantly between patients with and without SCLC, \nbut symptoms in patients with SCLC appeared within a shorter time-frame, \nindicating a more rapid clinical course. The presence of a particular symptom \nassociated with LEMS did not predict the presence of SCLC, but in patients with \nrapidly progressive LEMS the possibility of underlying lung cancer should be of \nparticular concern.",
"We report a case of paraneoplastic myasthenic syndrome with clinical features \nsuggesting Lambert Eaton syndrome but without the electromyographic elements \nrequired for diagnosis. Anti-calcium channel antibodies were also lacking. The \nelectromyogram evidenced a block and the Tensilon test was positive. The \nefficacy of anticholinesterases argued in favor of myasthenia but \nanti-acetylcholine receptor antibodies were negative. The block was more of a \nmixed nature, involving both presynaptic transmission as in Lambert Eaton \nsyndrome and post-synaptic transmission as in paraneoplastic myasthenia. The \nprimary tumor was identified as a small-cell neuroendocrine lung carcinoma on \nmediastinal biopsies obtained directly on CT-scan guided puncture of a \nmediastinal node. Thoracotomy was thus avoided. The Lambert Eaton syndrome is a \nparaneoplastic manifestation of small-cell lung cancer in 50% of the cases \nunlike generalized myasthenia which apparently is never associated with \nsmall-cell lung cancer. A mixed paraneoplastic neuro-muscle junction disorder \nwith aspects of each can be exceptionally observed.",
"Lambert-Eaton myasthenic syndrome (LEMS) is one of the neurologic paraneoplastic \nsyndromes often found in patients with lung cancer. It is characterized by a \ngeneralized deficit of neurotransmitter release. Patients with small cell lung \ncancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in \npatients affected by LEMS. LEMS is an autoimmune disease, and autoantibodies \nthat interfere with neurotransmitter release by binding to presynaptic \nvoltage-operated calcium channels (VOCCs) have been found in sera of patients \nwith LEMS. Both human neuronal and SCLC cell lines express \nomega-conotoxin-sensitive VOCCs, and autoantibodies from patients affected by \nLEMS can precipitate these channels. We have now screened a large population of \npatients and control subjects in order to define the specificity and sensitivity \nof the anti-VOCC antibody assay. We have tested sera from 52 patients with LEMS \nwith and without SCLC; 32 sera from patients with SCLC without LEMS, 31 from \npatients with non-SCLC, 34 from patients with inflammatory lung diseases, 17 \nfrom patients with other neurologic disorders, and 48 from healthy control \nsubjects. We have found that a positive result with this radioimmunoassay is \nhighly specific for LEMS, with or without SCLC, when the antibody titer is \nhigher than 14.21 pM. Anti-VOCC antibodies have also been found in about 40% of \npatients with SCLC without LEMS, but they were absent in all the other \npopulations tested. We can conclude that this serologic assay is a very useful \naid in the diagnosis of LEMS, and it might be useful also for the early \ndiagnosis of SCLC.",
"We have used human beta 2 and beta 4 cDNA probes to map the genes encoding two \nisoforms of the regulatory beta subunit of voltage-activated Ca2+ channels, viz. \nCACNB2 (beta 2) and CACNB4 (beta 4), to human chromosomes 10p12 and 2q22-q23, \nrespectively, by fluorescence in situ hybridization. The gene encoding the beta \n2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen \nin humans, is found close to a region that undergoes chromosome rearrangements \nin small cell lung cancer, which occurs in association with LEMS. CACNB2 (beta \n2) and CACNB4 (beta 4) genes are members of the ion-channel gene superfamily and \nit should now be possible to examine their loci by linkage analysis of \nion-channel-related disorders. To date, no such disease-related gene has been \nassigned to 10p12 and 2q22-q23.",
"We report a case of neuromuscular disease overlap between myasthenia gravis and \nLambert-Eaton syndrome (LES). Clinical features were those of LES and occurred \ninsidiously in this 68-year old man: proximal weakness predominant in the lower \nlimbs, generalized areflexia, dryness of the mouth and partial right eye palsy. \nInvestigations disclosed a small cell lung cancer. On the other hand, an \nelectrophysiological study showed low amplitude of all motor evoked potentials, \nand significant decrement in the median nerve at repeated 3 Hz stimulation, but \nfailed to disclose any increment of the motor evoked potential in abductor \ndigiti minimi pedis muscle after both maximal voluntary contraction and repeated \n20 Hz stimulation. In addition, the patient improved under anticholinesterase \ndrugs, but failed to respond to guanidine. Titres for both \nanti-acetylcholine-receptor antibodies and calcium channel antibodies were \nnegative. The relationship between our case and recently reported cases of \nco-existence of the Lambert-Eaton myasthenic syndrome and myasthenia gravis is \ndiscussed.",
"Plasma from patients with Lambert-Eaton myasthenic syndrome (LEMS), an \nautoimmune disease of neuromuscular transmission, contains antibodies that bind \nto the synaptic vesicle protein synaptotagmin. Synaptotagmin associates with \ncalcium channels and appears to regulate synaptic vesicle docking at the plasma \nmembrane prior to rapid neurotransmitter release. Autoantibodies directed \nagainst a synaptotagmin-calcium channel complex may be involved in the etiology \nof LEMS. In the majority of patients LEMS is associated with small cell lung \ncancer (SCLC). We have detected the expression of proteins of the secretory \npathway, including synaptotagmin, syntaxin and N-type calcium channels, in a \npanel of SCLC tumor lines. These observations are compatible with the hypothesis \nthat the initial autoimmune response in LEMS is triggered by the tumor.",
"Thirty years ago, antibodies against the muscle acetylcholine receptor (AChR) \nwere recognized as the cause of myasthenia gravis. Since then, there has been \ngreat interest in identifying other neurological disorders associated with \nautoantibodies. Several other antibody-mediated neuromuscular disorders have \nbeen identified, each associated with an antibody against a ligand- or \nvoltage-gated ion channel. The Lambert-Eaton syndrome is caused by antibodies \nagainst voltage-gated calcium channels and often occurs in patients with small \ncell lung cancer. Acquired neuromyotonia is caused by voltage-gated potassium \nchannel antibodies, and autoimmune autonomic ganglionopathy is caused by \nantibodies against the neuronal AChR in autonomic ganglia. There is good \nevidence that antibodies in these disorders cause changes in synaptic function \nor neuronal excitability by directly inhibiting ion channel function. More \nrecently, studies have identified ion channel antibodies in patients with \ncertain CNS disorders, such as steroid-responsive encephalitis and \nparaneoplastic cerebellar ataxia. It remains unclear if antibodies can gain \naccess to the CNS and directly cause ion channel dysfunction. Treatment of \nautoimmune channelopathies includes drugs that help restore normal neuronal \nfunction and treatments to remove pathogenic antibodies (plasma exchange) or \nmodulate the immune response (steroids or immunosuppressants). These disabling \nneurological disorders may be dramatically responsive to immunomodulatory \ntherapy. Future studies will likely lead to identification of other ion channel \nantibodies and other autoimmune channelopathies.",
"In the nervous system, voltage-gated Ca2+ channels regulate numerous processes \ncritical to neuronal function including secretion of neurotransmitters, \ninitiation of action potentials in dendritic regions of some neurons, growth \ncone elongation, and gene expression. Because of the critical role which Ca2+ \nchannels play in signaling processes within the nervous system, disruption of \ntheir function will lead to profound disturbances in neuronal function. \nVoltage-gated Ca2+ channels are the targets of several relatively rare \nneurological or neuromuscular diseases resulting from spontaneously-occurring \nmutations in genes encoding for parts of the channel proteins, or from \nautoimmune attack on the channel protein responses. Mutations in CACNAIA, which \nencodes for the alpha1A subunit of P/Q-type Ca2+ channels, lead to symptoms seen \nin familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar \nataxia type 6. Conversely, autoimmune attack on Ca2+ channels at motor axon \nterminals causes peripheral cholinergic nerve dysfunction observed in \nLambert-Eaton Myasthenic Syndrome (LEMS), the best studied of the disorders \ntargeting voltage-gated Ca2+ channels. LEMS is characterized by decreased evoked \nquantal release of acetylcholine (ACh) and disruption of the presynaptic active \nzones, the sites at which ACh is thought to be released. LEMS is generally \nbelieved to be due to circulating antibodies directed specifically at the Ca2+ \nchannels located at or near the active zone of motor nerve terminals (P/Q-type) \nand hence involved in the release of ACh. However, other presynaptic proteins \nhave also been postulated to be targets of the autoantibodies. LEMS has a high \ndegree of coincidence (approximately 60%) with small cell lung cancer; the \nremaining 40% of patients with LEMS have no detectable tumor. Diagnosis of LEMS \nrelies on characteristic patterns of electromyographic changes; these changes \nare observable at neuromuscular junctions of muscle biopsies from patients with \nLEMS. In the majority of LEMS patients, those having detectable tumor, the \ndisease is thought to occur as a result of immune response directed initially \nagainst voltage-gated Ca2+ channels found on the lung tumor cells. In these \npatients, effective treatment of the underlying tumor generally causes marked \nimprovement of the symptoms of LEMS as well. Animal models of LEMS can be \ngenerated by chronic administration of plasma, serum or immunoglobulin G to \nmice. These models have helped dramatically in our understanding of the \npathogenesis of LEMS. This \"passive transfer\" model mimics the \nelectrophysiological and ultrastructural findings seen in muscle biopsies of \npatients with LEMS. In this model, we have shown that the reduction in amplitude \nof Ca2+ currents through P/Q-type channels is followed by \"unmasking\" of an \nL-type Ca2+ current not normally found at the motor nerve terminal which \nparticipates in release of ACh from terminals of mice treated with plasma from \npatients with LEMS. It is unclear what mechanisms underlie the development of \nthis novel L-type Ca2+ current involved in release of ACh at motor nerve \nterminals during passive transfer of LEMS.",
"A patient with the Lambert-Eaton syndrome (LES) and small cell lung cancer \ndeveloped respiratory failure several hours after verapamil was given. \nImprovement in respiratory function did not occur when guanidine was given, but \nwas delayed until verapamil was discontinued 3 days later. Although other \nfactors may have contributed to the clinical deterioration of our patient, the \ntemporal relationship to verapamil and the theoretical danger of calcium channel \nblockade lead us to believe that the drug should be used cautiously in LES.",
"The sera of patients with Lambert-Eaton myasthenic syndrome (LEMS) contain \nautoantibodies against several extracellular and intracellular components of the \nvoltage-gated calcium channel (VGCC)/synaptic vesicle release complex. An \nexample of the latter are anti-beta-subunit antibodies (anti-MysB antibodies). \nWe constructed a full-length cDNA clone of a human VGCC beta-subunit to produce \npurified beta-subunit fusion protein (MysB protein). Using this protein, we \ndemonstrated that anti-beta-subunit antibodies are present in the sera of 23% of \nLEMS patients and only, in low titer, in 2% of small cell lung cancer patients \nwithout LEMS. The presence of anti-beta-subunit antibodies was closely \nassociated with high titers of P/Q- and N-type VGCC antibodies. Immunization of \nrats with the purified MysB protein induced high antibody titers, but no signs \nof neurologic dysfunction were found. We conclude that anti-beta-subunit \nantibodies are not likely to interfere with ion channel function, but their \npresence could explain the cross-reactivity of LEMS sera with several subtypes \nof VGCCs and the lack of correlation between anti-VGCC antibody titer and \nclinical severity of disease.",
"Sodium channels of human small-cell lung cancer (SCLC) cells were examined with \nwhole-cell and single-channel patch clamp methods. In the tumor cells from SCLC \ncell line NCI-H146, the majority of the voltage-gated Na+ channels are only \nweakly tetrodotoxin (TTX)-sensitive (Kd = 215 nM). With the membrane potential \nmaintained at -60 to -80 mV, these cells produced all-or-nothing action \npotentials in response to depolarizing current injection (> 20 pA). Similar \nall-or-nothing spikes were also observed with anodal break excitation. Removal \nof external Ca2+ did not affect the action potential production, whereas 5 \nmicroM TTX or substitution of Na+ with choline abolished it. Action potentials \nelicited in the Ca(2+)-free condition were reversibly blocked by 4 mM MnCl2 due \nto the Mn(2+)-induced inhibition of voltage-dependent sodium currents (INa). \nTherefore, Na+ channels, not Ca2+ channels, underlie the excitability of SCLC \ncells. Whole-cell INa was maximal with step-depolarizing stimulations to 0 mV, \nand reversed at +45.2 mV, in accord with the predicted Nernst equilibrium \npotential for a Na(+)-selective channel. INa evoked by depolarizing test \npotentials (-60 to +40 mV) exhibited a transient time course and \nactivation/inactivation kinetics typical of neuronal excitable membranes; the \nplot of the Hodgkin-Huxley parameters, m infinity and h infinity, also revealed \nbiophysical similarity between SCLC and neuronal Na+ channels. The single \nchannel current amplitude, as measured with the inside-out patch configuration, \nwas 1.0 pA at -20 mV with a slope conductance of 12.1 pS. The autoantibodies \nimplicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to \ninhibit ICa and INa in bovine adrenal chromaffin cells, also significantly \ninhibited INa in SCLC cells. These results indicate that (i) action potentials \nin human SCLC cells result from the regenerative increase in voltage-gated Na+ \nchannel conductance; (ii) fundamental characteristics of SCLC Na+ channels are \nthe same as the classical sodium channels found in a variety of excitable cells; \nand (iii) in some LES patients, SCLC Na+ channels are an additional target of \nthe pathological IgG present in the patients' sera.",
"The clinical and electrophysiological data of 18 consecutive adult patients with \nparaneoplastic Lambert-Eaton myasthenic syndrome (LMES) have been reviewed. The \ncancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and \nepidermoid lung carcinoma in 3 cases. The main clinical neurological features \nwere proximal lower limb weakness (100%), depressed tendon reflexes (94%) and \ndryness of the mouth (66%). The results of repetitive nerve stimulation (RNS) \nwere not statistically different in the paraneoplastic LEMS group and in a group \nof 6 LMS patients in whom no carcinoma had been detected. Low-amplitude compound \nmuscle action potential (CMAP) was present in all cases; decremental response at \nlow stimulation rates was present in 13/15 cases. An abnormal incremental \nresponse at high stimulation rates was observed in all cases. A close \ncorrelation between CMAP amplitude and clinical condition was found in 4 cases \nduring the long-term follow-up. In one patient the RNS electrical pattern could \nbe misinterpreted as myasthenia gravis in only one muscle tested. We underline \nthe usefulness of a 50 Hz stimulation during 4 seconds to establish the \ndiagnosis unequivocally, and that of post-exercise facilitation in routine \ndetection among an SCLC population. Our results suggest that CAMP amplitude and \nRNS test could be used to evaluate the short-term improvement of LMS under \ntreatment and, in some cases, for the long-term follow-up. The infraclinical \naxonal neuropathy detected in 8 patients probably was another associated \nautoimmune paraneoplastic complication.",
"1. Human small-cell lung cancer (SCLC) cells are believed to express the \nantigens responsible for the production of pathological antibodies in the \nLambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal \ntransmitter release from the motor nerve terminal is impaired. Whole-cell \npatch-clamp techniques were used to study the voltage-dependent Ca2+ channels \nexpressed by H146 SCLC cells and the effects of LES antibodies on these \nchannels. The types of Ca2+ channels were determined using biophysical \nproperties and pharmacological sensitivity to several antagonists. 2. Whole-cell \nCa2+ currents (ICa) in SCLC cells are sensitive to the dihydropyridine (DHP) \nnicardipine, omega-conotoxin GVIA (omega-CgTX GVIA) and omega-agatoxin IVA \n(omega-AgTX IVA). Nicardipine at 100 nM and 10 microM reduced ICa by 35 and 45% \n(n = 38 cells), respectively, while omega-CgTX GVIA (1 microM) inhibited ICa by \n32% (n = 31). Application of omega-AgTX IVA at 50 and 100 nM to the cancer cells \ndecreased ICa by 41 and 42%, respectively (n = 22). 3. Measurement of cell \nmembrane capacitance (Cm) revealed that Ca(2+)-dependent exocytosis underlies \nthe secretory activity of SCLC cells. Exocytosis, when induced by step \ndepolarizing pulses and measured by increases in Cm, was markedly inhibited by \nnicardipine (10 microM) and omega-AgTX IVA (100 nM). In contrast, omega-CgTX \nGVIA (1 microM) was not as effective in altering increases in Cm. 4. From \nnegative (-80 mV) and depolarized (-40 mV) holding potentials, both peak and \nplateau ICa were inhibited by the presence of LES antibodies (1 mg ml-1 IgG). \nLES serum also reduced depolarization-induced increases in Cm by 48% (n = 15). \n5. To determine whether the LES antibodies are downregulating a specific type(s) \nof Ca2+ channel, nicardipine (10 microM), omega-CgTX GVIA (1 microM) or \nomega-AgTX IVA (100 nM) was applied to tumour cells that had been previously \nexposed to LES serum for 24 h. The most pronounced change was that omega-AgTX \nIVA was 38-84% less effective at reducing ICa after the IgG treatment. The \neffectiveness of nicardipine was diminished by 18% after incubation with the LES \nantibodies, whereas the omega-CgTX GVIA was seen to be more effective. These \nresults suggest that LES IgG downregulates P-type Ca2+ channels and, possibly, \nto a lesser extent L-type channels. 6. In view of recent evidence that P-type \nCa2+ channels mediate cholinergic transmitter release at the mammalian \nneuromuscular junction (NMJ), the expression of P-type Ca2+ channels in the SCLC \ncells and the reactivity of LES IgG with these channels support the hypothesis \nthat P-type Ca2+ channels in these cancer cells may trigger the autoantibody \nproduction in this disorder. The antibodies so produced are implicated in the \nfunctional impairment of the Ca2+ channels characteristic of LES.",
"Lambert-Eaton syndrome (LES) is an immune-mediated disorder of the presynaptic \nneuromuscular junction due to the blocking effect of the voltage-gated calcium \nchannel (VGCC) antibodies. Small-cell lung cancer (SCLC) is the most common \ncause of LES. We report an unusual case of LES associated with large-cell \nneuroendocrine carcinoma (LCNEC) of the lung. In this case, clinical symptoms of \nLES predated the diagnosis of LCNEC by 6 years. After tumor resection, the \npatient experienced clinical and electrophysiological improvement. In addition, \nhe had a decrease in VGCC antibody titer from 130 to 80 pmol/L. The onset of LES \ncan be prolonged, and tumor surveillance should continue in these cases.",
"Paraneoplastic Lambert-Eaton myasthenia syndrome is presented in two cases with \nsmall cell lung cancer. An increase of serum cholinesterase activity was \nexplained by induced release of biologically active proteins by neoplastic \ntissue.",
"BACKGROUND/OBJECTIVE: We reported that 43% of patients with Lambert-Eaton \nmyasthenic syndrome (LEMS) and small cell lung cancer (SCLC) had an antibody \ncalled anti-glial nuclear antibody (AGNA), defined by the immunoreaction with \nthe nuclei of the Bergmann glia of the cerebellum. This study was undertaken to \nidentify the antigen recognized by AGNA and to confirm the association with \nparaneoplastic LEMS in a larger series.\nMETHODS: We probed a fetal brain cDNA library with AGNA-positive sera. The \npresence of antibodies against the isolated antigen was detected by immunoblot \nof phage plaques from two positive clones. We studied 105 patients with LEMS (55 \nwith SCLC), 50 with paraneoplastic neurologic syndromes, SCLC, and Hu \nantibodies, and 50 with only SCLC.\nRESULTS: Probing of the fetal brain expression library with AGNA sera resulted \nin the isolation of SOX1, a highly immunogenic tumor antigen in SCLC. IgG eluted \nfrom SOX1 clones produced the same cerebellar immunoreactivity as of AGNA sera. \nSOX1 antibodies were present in 64% of patients with LEMS and SCLC but in none \nof the 50 with idiopathic LEMS (p < 0.0001). Compared with paraneoplastic LEMS, \nthe frequency of SOX1 antibodies was significantly lower in patients with Hu \nantibodies (32%, p = 0.002) and in those with only SCLC (22%).\nCONCLUSIONS: SOX1 is the antigen recognized by anti-glial nuclear \nantibody-positive sera. The detection of SOX1 antibodies in patients with \nLambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell \nlung cancer and may be used to follow more closely those LEMS patients with no \nevidence of cancer at the initial workup.",
"Utilizing the whole-cell patch-clamp method we assessed the Ca2+ current (ICa) \nin well-established cell lines from human small-cell carcinoma (SCC) of the \nlung, NCI-H209 and NCI-H187. The Ca2+ current was readily observed in H209 \ntumour cells (90% of the cells tested), whereas H187 tumour cells only \noccasionally expressed Ca2+ channels (26% of the cells tested). H209 Ca2+ \ncurrent was evoked by potentials greater than -30 mV and exhibited partial \ninactivation over the duration of a 40 ms command potential. This inward current \nwas unchanged by alteration of the holding potential from -80 to -40 mV and the \nactivation phase of the Ca2+ current was best fitted by Hodgkin-Huxley m(t)2 \nkinetics. H209 Ca2+ current was reduced over 80% by verapamil (100 microM), \nwhereas w-conotoxin (5 microM) appeared to be without effect. In contrast, H209 \nCa2+ current was rapidly abolished by nifedipine (10 microM), strongly \nsuggesting the presence of L-type Ca2+ channels. Voltage-gated Ca2+ channels may \nbe important to the secretion of ectopic hormones and the etiology and \npathogenesis of Lambert-Eaton syndrome, an autoimmune disorder of the motor \nnerve terminal in which autoantibodies directed against voltage-gated Ca2+ \nchannels are produced.",
"Plasma and IgG obtained from 10 Lambert-Eaton myasthenic syndrome (LES) patients \n(5 with carcinoma, 5 without associated cancer), 6 healthy subjects, and 1 \npatient with small-cell lung cancer (SCLC) were examined in their ability to \nrecognize chromaffin cell antigens on Western blots. The pattern of antigen \nrecognition was compared with the magnitude of inhibition of voltage-dependent \ncalcium and sodium currents recorded with the patch-clamp technique from \nchromaffin cells. Eight of the 11 patients with LES and/or SCLC recognized \nplasma membrane proteins and 9 of the patients' IgG interacted with cytoplasmic \nantigens with no apparent pattern of antigen recognition between patients. Also, \nthere was no obvious band pattern distinguishing patients with LES from those \nwith LES and concurrent SCLC. Eighty percent of the LES patients' antibodies \nwere capable of reducing the calcium current (ICa) in chromaffin cells. One of \nthe novel findings of this study is that 30% of the patients had produced \nantibodies which were able to inhibit both calcium and sodium currents (INa). \nThe heterogeneous response of the IgG on the Western blots does not appear to \ncorrelate with the efficacy of reducing the inward currents.",
"Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder \ncharacterized by defective neurotransmitter release at presynaptic terminals. It \nis caused by an IgG autoantibody reacting against voltage-gated calcium \nchannels. Severe LEMS complicated by ventilatory failure is rare. We report a \ncase of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory \nfailure in a 67-year-old man who initially presented with progressive limb \nweakness for 6 months and tachypnea with shallow breathing for 1 week. LEMS was \ndiagnosed through electrophysiologic studies. Chest radiography and computerized \ntomography showed a huge mass lesion over the left anterior and middle \nmediastinum with an encasement of the left pulmonary artery. Cytologic \nexamination of ultrasound-guided fine needle aspiration disclosed SCLC. \nSuccessful treatment in combination with plasma exchange and chemotherapy \nresulted in dramatic tumor regression and LEMS remission, which were confirmed \nby chest radiography and electrophysiologic studies. This case suggests that \nplasma exchange and chemotherapy can be effective in treating SCLC with severe \nLEMS that produces ventilatory failure.",
"Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin \nwhich is often associated with anaplastic small-cell lung cancer. It seems to be \nan autoimmune disease responsible for a deficit of acetylcholine ejection in the \nmotor end plate. On the occasion of two recent cases, we review the clinical, \nphysiopathological and diagnostic aspects of this paraneoplastic syndrome.",
"LES is an autoimmune disorder of the neuromuscular junction in which \nautoantibodies directed against voltage-dependent Ca2+ channels block \nnerve-evoked Ca2+ entry at the motor nerve terminal. The pathogenic IgG is \nlikely to produce a similar inhibitory effect on the Ca2+ channel function in \nother cholinergic synapses of the autonomic nervous system. This pathophysiology \nis sufficient to account for the distinctive clinical, immunologic, and \nelectrophysiologic manifestations in patients with LES. Etiology of this disease \nis uncertain but in view of its frequent association with small cell lung \ncancer, this specific type of neoplasm may be implicated in the initiation of \nautoimmune response. Recent studies indeed support the possibility that the \nantigenic stimulus in the neoplastic form of LES may arise from \nvoltage-dependent Ca2+ channels found in the lung cancer cells.",
"Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder \ncaused by an IgG-mediated reduction in number of presynaptic voltage-gated \ncalcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, \nthe stimulus for antibody production may be VGCC on small cell lung cancer \n(SCLC). In this study membranes isolated from a human small cell lung cancer \nxenograft (Mar), that bound [3H]PN200-110, a VGCC antagonist, were subjected to \nWestern blotting using plasma from 12 LEMS patients and eight controls. Although \none band recognised by 3/12 LEMS IgGs might be associated with the VGCC, a \nnumber of other proteins were recognised both by LEMS plasma, and by plasma from \npatients with other disorders. The results illustrate the difficulties found \nusing Western blotting with autoimmune plasma to identify specific polypeptides \nin a crude antigen preparation."
] | ['http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015624', 'http://www.disease-ontology.org/api/metadata/DOID:3905', 'http://www.disease-ontology.org/api/metadata/DOID:1324', 'http://www.disease-ontology.org/api/metadata/DOID:0050214', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008175'] |
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] | train | Which type of myeloma is ixazomib being evaluated for? | factoid | The disease focus for the irreversible epoxyketone proteasome inhibitor ixazomib is multiple myeloma. | Multiple myeloma | [
"(18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed \ntomography (CT) are useful imaging modalities for evaluating tumor progression \nand treatment responses in genetically engineered mouse models of solid human \ncancers, but the potential of integrated FDG-PET/CT for assessing tumor \ndevelopment and new interventions in transgenic mouse models of human blood \ncancers such as multiple myeloma (MM) has not been demonstrated. Here we use \nBALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the \nwidely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an \nexcellent research tool for assessing interleukin-6- and MYC-driven plasma cell \ntumor (PCT) development in a serial, reproducible and stage- and lesion-specific \nmanner. We also show that FDG-PET/CT permits determination of objective drug \nresponses in PCT-bearing mice treated with the investigational proteasome \ninhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate \n(MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival \nof 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One \noutlier mouse presented with primary refractory disease. Our findings \ndemonstrate the utility of FDG-PET/CT for preclinical MM research and suggest \nthat this method will play an important role in the design and testing of new \napproaches to treat myeloma.",
"Ixazomib is the first investigational oral proteasome inhibitor to be studied \nclinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple \nmyeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, \nthalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) \nreceived single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day \ncycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) \noccurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 \npatients received in 4 expansion cohorts. Patients received a median of 4 cycles \n(range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related \nadverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), \nand rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and \nneutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% \n(no grade ≥3). Two patients died on the study (both considered unrelated to \ntreatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma \nexposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 \nresponse-evaluable patients, 15% achieved partial response or better (76% stable \ndisease or better). These findings have informed the subsequent clinical \ndevelopment of ixazomib in multiple myeloma. This trial was registered at \nwww.clinicaltrials.gov as #NCT00932698.",
"Proteasome inhibition represents one of the more important therapeutic targets \nin the treatment of multiple myeloma (MM), since by suppressing nuclear \nfactor-κB activity, which promotes myelomagenesis, it makes plasma cells \nsusceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor \napproved for MM therapy, has been shown to increase response rate and improve \noutcome in patients with relapsed/refractory disease and in the frontline \nsetting, particularly when combined with immunomodulatory drugs and alkylating \nagents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the \nfirst oral compound to be evaluated for the treatment of MM. Ixazomib has shown \nimproved pharmacokinetic and pharmacodynamic parameters compared with \nbortezomib, in addition to similar efficacy in the control of myeloma growth and \nprevention of bone loss. Ixazomib was found to overcome bortezomib resistance \nand to trigger synergistic antimyeloma activity with dexamethasone, \nlenalidomide, and histone deacetylase inhibitors. Phase I/II studies using \nixazomib weekly or twice weekly in relapsed/refractory MM patients suggested \nantitumor activity of the single agent, but more promising results have been \nobtained with the combination of ixazomib, lenalidomide, and dexamethasone in \nnewly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a \nsingle agent, showing important activity in this difficult-to-treat plasma-cell \ndyscrasia. More frequent side effects observed during administration of ixazomib \nwere thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas \nsevere peripheral neuropathy was rare. Here, we review the chemical \ncharacteristics of ixazomib, as well as its mechanism of action and results from \npreclinical and clinical trials.",
"Inhibition of proteasome, a proteolytic complex responsible for the degradation \nof ubiquitinated proteins, has emerged as a powerful strategy for treatment of \nmultiple myeloma (MM), a plasma cell malignancy. First-in-class agent, \nbortezomib, has demonstrated great positive therapeutic efficacy in MM, both in \npre-clinical and in clinical studies. However, despite its high efficiency, a \nlarge proportion of patients do not achieve sufficient clinical response. \nTherefore, the development of a second-generation of proteasome inhibitors (PIs) \nwith improved pharmacological properties was needed. Recently, several of these \nnew agents have been introduced into clinics including carfilzomib, marizomib \nand ixazomib. Further, new orally administered second-generation PI oprozomib is \nbeing investigated. This review provides an overview of main mechanisms of \naction of PIs in MM, focusing on the ongoing development and progress of novel \nanti-proteasome therapeutics.",
"BACKGROUND: The combination of bortezomib, lenalidomide, and dexamethasone is a \nhighly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an \ninvestigational, oral, proteasome inhibitor with promising anti-myeloma effects \nand low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess \nthe safety, tolerability, and activity of ixazomib in combination with \nlenalidomide and dexamethasone in newly diagnosed multiple myeloma.\nMETHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 \nyears or older with measurable disease, Eastern Cooperative Oncology Group \nperformance status 0-2, and no grade 2 or higher peripheral neuropathy, and \ntreated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days \n1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, \nfollowed by maintenance therapy with ixazomib alone. In phase 1, we gave \npatients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the \nrecommended dose for phase 2. The primary endpoints were maximum tolerated dose \nfor phase 1, and the rate of very good partial response or better for phase 2. \nSafety analyses were done in all patients who received at least one dose of \nstudy drug; efficacy analyses were done in all patients who received at least \none dose of study drug at the phase 2 dose, had measurable disease at baseline, \nand had at least one post-baseline response assessment. This study is registered \nat ClinicalTrials.gov, number NCT01217957.\nFINDINGS: Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to \nphase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase \n1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The \nmaximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the \nrecommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed \ndose based on population pharmacokinetic results. Grade 3 or higher adverse \nevents related to any drug were reported in 41 (63%) patients, including skin \nand subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight \npatients, 12%), and thrombocytopenia (five patients, 8%); drug-related \nperipheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five \npatients discontinued because of adverse events. In 64 response-evaluable \npatients, 37 (58%, 95% CI 45-70) had a very good partial response or better.\nINTERPRETATION: The all-oral combination of weekly ixazomib plus lenalidomide \nand dexamethasone was generally well tolerated and appeared active in newly \ndiagnosed multiple myeloma. These results support the phase 3 trial development \nof this combination for multiple myeloma.\nFUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda \nPharmaceutical International Company.",
"In spite of significant advances in the management of multiple myeloma (MM), the \ndisease remains incurable and nearly all patients ultimately relapse and require \nsalvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a \ncritical area of research pertaining to biological mechanisms of progression and \nchemotherapy resistance, as well as to the development of new pharmacologic \nagents and immunologic approaches for the disease. The immunomodulatory agents \nand proteasome inhibitors represent the cornerstone of treatment in this \nsetting, with combination regimens incorporating these drugs demonstrating \nencouraging rates and duration of response, including the newer agents, \npomalidomide and carfilzomib. In addition, novel drug classes have shown \npromising activity in RR MM, including the orally-administered proteasome \ninhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 \nmonoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; \nand histone deacetylase inhibitors such as panobinostat and rocilinostat.",
"Multiple myeloma (MM) is with an incidence of 4-6/100 000 inhabitants a fairly \nfrequent malignancy of B cells. The incidence increases markedly with age. In \nthis review changes in the treatment of relapsed / refractory myeloma during the \nlast decade have been analysed. The present standard of care in the progressive \nor refractory myeloma was elaborated by the working group \"Refractory Multiple \nMyeloma\" using an extensive literature search for studies published between 2003 \nand 2013. Outside of clinical trials, high-dose therapy with stem cell \ntransplantation is recommended in fit patients up to 75 years without \nsignificant comorbidities. Ongoing studies address the question about the least \ntoxic and the most effective treatment. Therefore, inclusion of patients in \ntherapeutic trials and use of novel agent combinations is highly recommended, \ne.g. with 3(rd) generation-IMIDs (pomalidomide), new proteasome inhibitors, such \nas carfilzomib, ixazomib or oprozomib, antibodies, such as elotuzumab, \ndaratumumab or SAR650984, siltuximab, tabalumab, denosumab, romosozumab, BTK-, \nHSP-inhibitors and other innovative phase I/II agents.\nCONCLUSION: Based on new insights in the pathogenesis of the disease, treatment \noptions for MM have changed significantly in recent years. There is a \nsignificantly larger treatment diversity, i.e. more MM-active agents and \ncombinations are available today. Even with relapsed MM, patients with the \ndisease often live longer and have fewer complications.",
"Proteasome inhibitors have a 20 year history in cancer therapy. The first \nproteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple \nmyeloma treatment, moved rapidly through development from bench in 1994 to first \napproval in 2003. Bortezomib is a reversible boronic acid inhibitor of the \nchymotrypsin-like activity of the proteasome. Next generation proteasome \ninhibitors include carfilzomib and oprozomib which are irreversible epoxyketone \nproteasome inhibitors; and ixazomib and delanzomib which are reversible boronic \nacid proteasome inhibitors. Two proteasome inhibitors, bortezomib and \ncarfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage \nclinical trials. All of the agents are potent cytotoxics. The disease focus for \nall the proteasome inhibitors is multiple myeloma. This focus arose from \nclinical observations made in bortezomib early clinical trials. Later \npreclinical studies confirmed that multiple myeloma cells were indeed more \nsensitive to proteasome inhibitors than other tumor cell types. The discovery \nand development of the proteasome inhibitor class of anticancer agents has \nprogressed through a classic route of serendipity and scientific investigation. \nThese agents are continuing to have a major impact in their treatment of \nhematologic malignancies and are beginning to be explored as potential treatment \nagent for non-cancer indications.",
"Proteasome inhibition is an effective treatment strategy for multiple myeloma. \nWith improving survival, attention is increasingly focusing on ease of \nadministration and toxicity profile. Ixazomib is an investigational, orally \nbioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or \nrefractory multiple myeloma were enrolled on this phase 1 trial to evaluate \nsafety and tolerability and determine the maximum tolerated dose (MTD) of \nsingle-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD \ndetermination, patients were enrolled to 4 different cohorts based on \nrelapsed/refractory status and prior bortezomib and carfilzomib exposure. The \nMTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 \nnausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 \npatient. Common drug-related adverse events were thrombocytopenia (43%), \ndiarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed \nrate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine \n(18%) patients achieved a partial response or better, including 8 of 30 (27%) \nevaluable patients treated at the MTD. Pharmacokinetic studies suggested a long \nterminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This \ntrial was registered at www.clinicaltrials.gov as #NCT00963820.",
"PURPOSE: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically \nactive MLN2238 (ixazomib), is a next-generation proteasome inhibitor with \ndemonstrated preclinical and clinical antimyeloma activity, but yet with an \nunknown effect on myeloma bone disease. Here, we investigated its bone anabolic \nand antiresorptive effects in the myeloma setting and in comparison with \nbortezomib in preclinical models.\nEXPERIMENTAL DESIGN: The in vitro effect of MLN2238 was tested on osteoclasts \nand osteoclast precursors from healthy donors and patients with myeloma, and on \nosteoprogenitors derived from bone marrow mesenchymal stem cells also from both \norigins. We used an in vivo model of bone marrow-disseminated human myeloma to \nevaluate MLN2238 antimyeloma and bone activities.\nRESULTS: Clinically achievable concentrations of MLN2238 markedly inhibited in \nvitro osteoclastogenesis and osteoclast resorption; these effects involved \nblockade of RANKL (receptor activator of NF-κB ligand)-induced NF-κB activation, \nF-actin ring disruption, and diminished expression of αVβ3 integrin. A similar \nrange of MLN2238 concentrations promoted in vitro osteoblastogenesis and \nosteoblast activity (even in osteoprogenitors from patients with myeloma), \npartly mediated by activation of TCF/β-catenin signaling and upregulation of the \nIRE1 component of the unfolded protein response. In a mouse model of bone \nmarrow-disseminated human multiple myeloma, orally administered MLN2238 was \nequally effective as bortezomib to control tumor burden and also provided a \nmarked benefit in associated bone disease (sustained by both bone anabolic and \nanticatabolic activities).\nCONCLUSION: Given favorable data on pharmacologic properties and emerging \nclinical safety profile of MLN9708, it is conceivable that this proteasome \ninhibitor may achieve bone beneficial effects in addition to its antimyeloma \nactivity in patients with myeloma.",
"Multiple myeloma is still an incurable disease with pattern of regression and \nremission followed by multiple relapses raising from the residual myeloma cells \nsurviving even in the patients who achieve complete clinical response to \ntreatment. New antimyeloma drugs such as thalidomide, lenalidomide, and \nbortezomib have dramatically changed treatment paradigm leading to both tumor \nreduction and tumor suppression. Much progress has been made, but still many \nunsolved questions remain. In the mode of sequencing treatment for patients with \nmultiple myeloma, we are still using old drugs such as the alkylating agent \nmelphalan, which continues to play a central role in the transplantation \nsetting. Newer drugs are now emerging and are being tested: monoclonal \nantibodies, histone deacetylase (romidespsin), MLN9708 (ixazomib) a new oral \nproteasome inhibitor, carfilzomib, signal transduction modulator perifosine. \nMany advances have been made, but there is still a long way to go."
] | ['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009101'] |
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] | train | Which type of pluripotency is Otx2 associated with? | factoid | transcription factor Otx2 acts as a negative switch in the regulation of transition from naive to primed pluripotency. Otx2 and Oct4 drive early activation during embryonic stem cell transition from naive pluripotency. | formative pluripotency | [
"Reported pig induced pluripotent stem cells (piPSCs) have shown either a \nbFGF-dependent state with human embryonic stem cell (ESC) and mouse epiblast \nstem cell (EpiSC) morphology and molecular features or piPSCs exist in a \nLIF-dependent state and resemble fully reprogrammed mouse iPSCs. The features of \nauthentic piPSCs and molecular events during the reprogramming are largely \nunknown. In this study, we assessed the transcriptome profile of multiple piPSC \nlines derived from different laboratories worldwide and compared to mouse and \nhuman iPSCs to determine the molecular signaling pathways that might play a \ncentral role in authentic piPSCs. The results demonstrated that the \nup-regulation of endogenous epithelial cells adhesion molecule (EpCAM) was \ncorrelated with the pluripotent state of pig pluripotent cells, which could be \nutilized as a marker for evaluating pig cell reprogramming. Comparison of key \nsignaling pathways JAK-STAT, NOTCH, TGFB1, WNT and VEGF in pig, mouse and human \niPSCs showed that the core transcriptional network to maintain pluripotency and \nself-renewal in pig were different from that in mouse, but had significant \nsimilarities to human. Pig iPSCs, which lacked expression of specific naïve \nstate markers KLF2/4/5 and TBX3, but expressed the primed state markers of Otx2 \nand Fabp7, share defining features with human ESCs and mouse EpiSCs. The cluster \nof imprinted genes delineated by the delta-like homolog 1 gene and the type III \niodothyronine deiodinase gene (DLK1-DIO3) were silenced in piPSCs as previously \nseen in mouse iPSCs that have limited ability to contribute to chimaeras. These \nkey differences in naïve state gene and imprinting gene expression suggests that \nso far known piPSC lines may be more similar to primed state cells. The primed \nstate of these cells may potentially explain the rare ability of piPSCS to \ngenerate chimeras and cloned offspring.",
"The transcription factor Otx2 acts as a negative switch in the regulation of \ntransition from naive to primed pluripotency in mouse pluripotent stem cells. \nHowever, the molecular features and function of porcine OTX2 have not been well \nelucidated in porcine-induced pluripotent stem cells (piPSCs). By studying \nhigh-throughput transcriptome sequencing and interfering endogenous OTX2 \nexpression, we demonstrate that OTX2 is able to downgrade the self-renewal of \npiPSCs. OTX2 is highly expressed in porcine brain, reproductive tissues, and \npreimplantation embryos, but is undetectable in fibroblasts and most somatic \ntissues. However, the known piPSC lines reported previously produced different \nlevels of OTX2 depending on the induction procedures and culture conditions. \nOverexpression of porcine OTX2 can reduce the percentage of alkaline \nphosphatase-positive colonies and downregulate NANOG and OCT4 expression. In \ncontrast, knockdown of OTX2 can significantly increase endogenous expressions of \nNANOG, OCT4, and ESRRB, and stabilize the pluripotent state of piPSCs. On the \nother hand, NANOG can directly bind to the OTX2 promoter as shown in ChIP-seq \ndata and repress OTX2 promoter activity in a dose-dependent manner. These \nobservations indicate that OTX2 and NANOG can form a negative feedback circuitry \nto regulate the pluripotency of porcine iPS cells.",
"Mouse embryonic stem cells (ESCs) and the inner cell mass (ICM)-derived epiblast \nexhibit naive pluripotency. ESC-derived epiblast stem cells (EpiSCs) and the \npostimplantation epiblast exhibit primed pluripotency. Although core \npluripotency factors are well-characterized, additional regulators, including \nOtx2, recently have been shown to function during the transition from naive to \nprimed pluripotency. Here we uncover a role for Otx2 in the control of the naive \npluripotent state. We analyzed Otx2-binding activity in ESCs and EpiSCs and \nidentified Nanog, Oct4, and Sox2 as direct targets. To unravel the Otx2 \ntranscriptional network, we targeted the strongest Otx2-binding site in the \nNanog promoter, finding that this site modulates the size of specific \nESC-subtype compartments in cultured cells and promotes Nanog expression \nin vivo, predisposing ICM differentiation to epiblast. Otx2-mediated Nanog \nregulation thus contributes to the integrity of the ESC state and cell lineage \nspecification in preimplantation development.",
"Author information:\n(1)Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam, \nRotterdam, The Netherlands.\n(2)Department of Molecular Biology, Faculty of Science, Radboud University, \nRadboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The \nNetherlands.\n(3)Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, \nErasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.\n(4)Center for Biomics, Erasmus MC, University Medical Center Rotterdam, \nRotterdam, The Netherlands.\n(5)The Francis Crick Institute, London, UK.\n(6)Department for Neuromuscular Diseases, UCL Queen Square Institute of \nNeurology, London, UK.\n(7)Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, \nGermany.\n(8)Department of Laboratory Medicine, Laboratory of Hematology, Radboud \nUniversity, Nijmegen Medical Centre and Radboud Institute for Molecular Life \nSciences (RIMLS), Nijmegen, The Netherlands.\n(9)Institute of Molecular Biotechnology of the Austrian Academy of Sciences, \nVienna Biocenter (VBC), Vienna, Austria.\n(10)Department of Developmental Biology, Erasmus MC, University Medical Center \nRotterdam, Rotterdam, The Netherlands.\n(11)Department of Cell Biology, Erasmus MC, University Medical Center Rotterdam, \nRotterdam, The Netherlands. d.tenberge@erasmusmc.nl.\n(#)Contributed equally",
"Porcine OTX2 was found to be highly activated in porcine iPS cells (piPSCs) that \nwere reported by different laboratories worldwide. To reveal the regulatory \nfunction of OTX2 in porcine reprogrammed cells, we screened porcine miRNA-seq \ndatabases and found two miRNAs, miR-1343 and miR-545, that could specifically \nbind to 3'UTR of OTX2 and suppress endogenous OTX2 expression in piPSCs. \nKnockdown of OTX2 by miR-1343 and miR-545 could significantly increase the \nexpression of SOX2 and ESRRB, but did not alter the expressions of OCT4 and \nKLF4, and improve the pluripotency of piPSCs. The promoter-based assays showed \nthat OTX2 potentially bound to the promoter region of SOX2 and ESRRB and \nsuppressed their expression. On the other hand, SOX2 could interact with OTX2 \npromoter. Ectopic expression of SOX2 could significantly decrease OTX2 promoter \nactivity, showing that there is a negative feedback loop between SOX2 and OTX2. \nAdditionally, SOX2 and ESRRB significantly stimulated miR-1343 expression in \npiPSCs, but OTX2 down regulated the expression of miR-1343 in either direct or \nindirect manners. In summary, this study demonstrates that there is a regulatory \nnetwork mediated by miR-1343, in which downregulation of OTX2 by miR-1343 can \nelevate the expression of pluripotent genes that were then sustain the \npluripotency of piPSCs.",
"Embryonic stem cells (ESCs) cultured in leukemia inhibitory factor (LIF) plus \nfetal bovine serum (FBS) exhibit heterogeneity in the expression of naive and \nprimed transcription factors. This heterogeneity reflects the dynamic condition \nof ESCs and their versatility to promptly respond to signaling effectors \npromoting naive or primed pluripotency. Here, we report that ESCs lacking Nanog \nor overexpressing Otx2 exhibit an early primed identity in LIF + FBS and fail to \nconvert into 2i-induced naive state. Conversely, Otx2-null ESCs possess naive \nidentity features in LIF + FBS similar to Nanog-overexpressing ESCs and convert \npoorly into FGF-induced early primed state. When both Nanog and Otx2 are \ninactivated, ESCs cultured in LIF + FBS exhibit primed identity and weakened \nability to convert into naive state. These data suggest that, through mutual \nantagonism, NANOG and OTX2 specify the heterogeneous identity of ESCs cultured \nin LIF + FBS and individually predispose them for optimal response to naive or \nprimed inducing factors.",
"Mouse embryonic stem cells (ESCs) represent the naïve ground state of the \npreimplantation epiblast and epiblast stem cells (EpiSCs) represent the primed \nstate of the postimplantation epiblast. Studies have revealed that the ESC state \nis maintained by a dynamic mechanism characterized by cell-to-cell spontaneous \nand reversible differences in sensitivity to self-renewal and susceptibility to \ndifferentiation. This metastable condition ensures indefinite self-renewal and, \nat the same time, predisposes ESCs for differentiation to EpiSCs. Despite \nconsiderable advances, the molecular mechanism controlling the ESC state and \npluripotency transition from ESCs to EpiSCs have not been fully elucidated. Here \nwe show that Otx2, a transcription factor essential for brain development, plays \na crucial role in ESCs and EpiSCs. Otx2 is required to maintain the ESC \nmetastable state by antagonizing ground state pluripotency and promoting \ncommitment to differentiation. Furthermore, Otx2 is required for ESC transition \ninto EpiSCs and, subsequently, to stabilize the EpiSC state by suppressing, in \npluripotent cells, the mesendoderm-to-neural fate switch in cooperation with \nBMP4 and Fgf2. However, according to its central role in neural development and \ndifferentiation, Otx2 is crucially required for the specification of ESC-derived \nneural precursors fated to generate telencephalic and mesencephalic neurons. We \npropose that Otx2 is a novel intrinsic determinant controlling the functional \nintegrity of ESCs and EpiSCs.",
"Naive and primed pluripotency is characterized by distinct signaling \nrequirements, transcriptomes, and developmental properties, but both cellular \nstates share key transcriptional regulators: Oct4, Sox2, and Nanog. Here, we \ndemonstrate that transition between these two pluripotent states is associated \nwith widespread Oct4 relocalization, mirrored by global rearrangement of \nenhancer chromatin landscapes. Our genomic and biochemical analyses identified \ncandidate mediators of primed state-specific Oct4 binding, including Otx2 and \nZic2/3. Even when differentiation cues are blocked, premature Otx2 \noverexpression is sufficient to exit the naive state, induce transcription of a \nsubstantial subset of primed pluripotency-associated genes, and redirect Oct4 to \npreviously inaccessible enhancer sites. However, the ability of Otx2 to engage \nnew enhancer regions is determined by its levels, cis-encoded properties of the \nsites, and the signaling environment. Our results illuminate regulatory \nmechanisms underlying pluripotency and suggest that the capacity of \ntranscription factors such as Otx2 and Oct4 to pioneer new enhancer sites is \nhighly context dependent.",
"Directed differentiation of human induced pluripotent stem cells (iPSCs) into \nretinal pigmented epithelium (RPE) holds great promise in cell replacement \ntherapy for patients suffering from degenerative eye diseases, including \nage-related macular degeneration (AMD). In this study, we generated iPSCs from \nhuman dermal fibroblasts (HDFs) by electroporation with episomal plasmid vectors \nencoding OCT4, SOX2, KLF4, L-MYC together with p53 suppression. Intriguingly, \ncell reprogramming resulted in a metastable transcriptional activation and \nselective demethylation of neural and retinal specification-associated genes, \nsuch as OTX2, RX1 and SIX3. In contrast, RPE progenitor genes were \ntranscriptionally silent in HDFs and descendant iPSCs. Overexpression of OCT4 \nand SOX2 directly stimulated the expression of OTX2, RX1 and SIX3 in HDFs and \niPSCs. Luciferase and chromatin immunoprecipitation (ChIP) assays further \nidentified an OCT4- and two SOX2-binding sites located in the proximal promoter \nof OTX2. Histone acetylation and methylation on the local promoter also \nparticipated in the reactivation of OTX2. The transcriptional conversion of RX1 \nand SIX3 genes partially attributed to DNA demethylation. Subsequently, iPSCs \nwere induced into the RPE cells displaying the characteristics of polygonal \nshapes and pigments, and expressing typical RPE cell markers. Taken together, \nour results establish readily efficient and safe protocols to produce iPSCs and \niPSC-derived RPE cells, and underline that the reactivation of anterior neural \ntranscription factor OTX2, eye field transcription factor RX1 and SIX3 in iPSCs \nis a feature of pluripotency acquisition and predetermines the potential of RPE \ndifferentiation.",
"Development of multifunctional transcriptional activators is of increasing \nimportance as they could trigger complicated gene networks. Recently, we \ndeveloped a differential gene activating multifunctional small molecule SAHA-PIP \n(Sδ) by conjugating a histone deacetylase (HDAC) inhibitor, SAHA, to a selective \nDNA-binding pyrrole-imidazole polyamide (PIP). Epigenetic activity of Sδ was \nattributed to the active metal-binding (-NHOH) domain of SAHA. We synthesized a \nderivative of Sδ, called Jδ to evaluate the role of surface recognition domain \n(-phenyl) of SAHA in Sδ-mediated transcriptional activation. In vitro studies \nrevealed that Jδ displayed potent inhibitory activity against HDAC8. Jδ retained \nthe pluripotency gene-inducing ability of Sδ when used alone and in combination \nwith Sδ; a notable increase in the pluripotency gene expression was observed. \nInterestingly, Jδ significantly induced the expression of HDAC8-controlled Otx2 \nand Lhx1. Our results suggest that the epigenetic activity of our \nmultifunctional molecule could be altered to improve its efficiency as a \ntranscriptional activator for intricate gene network(s).",
"The enhancer landscape is dramatically restructured as naive preimplantation \nepiblasts transition to the post-implantation state of primed pluripotency. \nA key factor in this process is Otx2, which is upregulated during the early \nstages of this transition and ultimately recruits Oct4 to a different set of \nenhancers. In this study, we discover that the acetylation status of Oct4 \nregulates the induction of the primed pluripotency gene network. Maintenance of \nthe naive state requires the NAD-dependent deacetylase, SirT1, which \ndeacetylates Oct4. The activity of SirT1 is reduced during the naive-to-primed \ntransition; Oct4 becomes hyper-acetylated and binds to an Otx2 enhancer to \ninduce Otx2 expression. Induction of Otx2 causes the reorganization of \nacetylated Oct4 and results in the induction of the primed pluripotency gene \nnetwork. Regulation of Oct4 by SirT1 may link stem cell development to \nenvironmental conditions, and it may provide strategies to manipulate epiblast \ncell state.",
"Lin28 RNA-binding proteins play important roles in pluripotent stem cells, but \nthe regulation of their expression and the mechanisms underlying their functions \nare still not definitively understood. Here we address the above-mentioned \nissues in the first steps of mouse embryonic stem cell (ESC) differentiation. We \nobserved that the expression of Lin28 genes is transiently induced soon after \nthe exit of ESCs from the naive ground state and that this induction is due to \nthe Hmga2-dependent engagement of Otx2 with enhancers present at both Lin28 gene \nloci. These mechanisms are crucial for Lin28 regulation, as demonstrated by the \nabolishment of the Lin28 accumulation in Otx2- or Hmga2-knockout cells compared \nto the control cells. We have also found that Lin28 controls Hmga2 expression \nlevels during ESC differentiation through a let-7-independent mechanism. Indeed, \nwe found that Lin28 proteins bind a highly conserved element in the 3' UTR of \nHmga2 mRNA, and this provokes a down-regulation of its translation. This \nmechanism prevents the inappropriate accumulation of Hmga2 that would modify the \nproliferation and physiological apoptosis of differentiating ESCs. In summary, \nwe demonstrated that during ESC differentiation, Lin28 transient induction is \ndependent on Otx2 and Hmga2 and prevents an inappropriate excessive rise of \nHmga2 levels.-Parisi, S., Passaro, F., Russo, L., Musto, A., Navarra, A., \nRomano, S., Petrosino, G., Russo, T. Lin28 is induced in primed embryonic stem \ncells and regulates let-7-independent events.",
"Sall1 is a multi-zinc finger transcription factor that regulates kidney \norganogenesis. It is considered to be a transcriptional repressor, \npreferentially localized on heterochromatin. Mutations or deletions of the human \nSALL1 gene are associated with the Townes-Brocks syndrome. Despite its high \nexpression, no function was yet assigned for Sall1 in embryonic stem (ES) cells. \nIn the present study, we show that Sall1 is expressed in a \ndifferentiation-dependent manner and physically interacts with Nanog and Sox2, \ntwo components of the core pluripotency network. Genome-wide mapping of \nSall1-binding loci has identified 591 genes, 80% of which are also targeted by \nNanog. A large proportion of these genes are related to self-renewal and \ndifferentiation. Sall1 positively regulates and synergizes with Nanog for gene \ntranscriptional regulation. In addition, our data show that Sall1 suppresses the \nectodermal and mesodermal differentiation. Specifically, the induction of the \ngastrulation markers T brachyury, Goosecoid, and Dkk1 and the neuroectodermal \nmarkers Otx2 and Hand1 was inhibited by Sall1 overexpression during embryoid \nbody differentiation. These data demonstrate a novel role for Sall1 as a member \nof the transcriptional network that regulates stem cell pluripotency.",
"Naïve and primed pluripotent stem cells (PSCs) reflect discrete pluripotent \nstates that approximate the inner cell mass or the progressively \nlineage-restricted perigastrulation epiblast, respectively. Cells that occupy \nprimed pluripotency have distinct epigenetic landscapes, transcriptional \ncircuitry, and trophic requirements compared with their naïve counterparts. The \nexistence of multiple pluripotent states has not been explored in dogs, which \nshow promise as outbred biomedical models with more than 300 inherited diseases \nthat also afflict humans. However, our understanding of canine embryogenesis and \nembryo-derived stem cells is limited. Herein, we converted leukemia inhibitory \nfactor (LIF)-dependent and fibroblast growth factor 2 (FGF2)-dependent canine \nembryonic stem cells (cESCs) resembling primed PSCs toward a naïve pluripotent \nstate using LIF and inhibitors of glycogen synthase kinase 3β and \nmitogen-activated protein kinase kinase 1/2 [called 2i and LIF (2iL)]. cESCs \npropagated in 2iL exhibited significant induction of genes associated with the \nnaïve pluripotent state (eg, REX1, TBX3) and downregulation of primed \npluripotency markers (eg, OTX2, FGF5) (P < 0.05). Differential phosphorylation \nof signal transducer and activator of transcription 3 (STAT3) and cell fate \ndecisions on exposure to bone morphogenetic protein 4 (BMP4) suggested that a \nnovel pluripotent identity has been established with 2iL. Accordingly, cESCs \ncultured with 2iL formed colonies at a greater efficiency than LIF-FGF2 cESCs \nfollowing single-cell dissociation. Total genomic DNA methylation and histone H3 \nlysine 27 trimethylation signals were reduced in 2iL-treated cESCs. Our data \nsuggest that 2iL culture conditions promote the conversion of cESCs toward an \nepigenetically distinct pluripotent state resembling naïve PSCs.",
"The mouse embryo is the canonical model for mammalian preimplantation \ndevelopment. Recent advances in single cell profiling allow detailed analysis of \nembryogenesis in other eutherian species, including human, to distinguish \nconserved from divergent regulatory programs and signalling pathways in the \nrodent paradigm. Here, we identify and compare transcriptional features of \nhuman, marmoset and mouse embryos by single cell RNA-seq. Zygotic genome \nactivation correlates with the presence of polycomb repressive complexes in all \nthree species, while ribosome biogenesis emerges as a predominant attribute in \nprimate embryos, supporting prolonged translation of maternally deposited RNAs. \nWe find that transposable element expression signatures are species, stage and \nlineage specific. The pluripotency network in the primate epiblast lacks certain \nregulators that are operative in mouse, but encompasses WNT components and genes \nassociated with trophoblast specification. Sequential activation of GATA6, SOX17 \nand GATA4 markers of primitive endoderm identity is conserved in primates. \nUnexpectedly, OTX2 is also associated with primitive endoderm specification in \nhuman and non-human primate blastocysts. Our cross-species analysis demarcates \nboth conserved and primate-specific features of preimplantation development, and \nunderscores the molecular adaptability of early mammalian embryogenesis.",
"Author information:\n(1)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA; Falk Brain Tumor Center, Ann & Robert H Lurie \nChildren's Hospital of Chicago Research Center, Ann & Robert H Lurie Children's \nHospital of Chicago, Northwestern University Feinberg School of Medicine, \nChicago, IL, USA. Electronic address: s-malchenko@northwestern.edu.\n(2)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA; Falk Brain Tumor Center, Ann & Robert H Lurie \nChildren's Hospital of Chicago Research Center, Ann & Robert H Lurie Children's \nHospital of Chicago, Northwestern University Feinberg School of Medicine, \nChicago, IL, USA. Electronic address: JXie@luriechildrens.org.\n(3)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA; Falk Brain Tumor Center, Ann & Robert H Lurie \nChildren's Hospital of Chicago Research Center, Ann & Robert H Lurie Children's \nHospital of Chicago, Northwestern University Feinberg School of Medicine, \nChicago, IL, USA. Electronic address: mbonaldo@luriechildrens.org.\n(4)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA; Falk Brain Tumor Center, Ann & Robert H Lurie \nChildren's Hospital of Chicago Research Center, Ann & Robert H Lurie Children's \nHospital of Chicago, Northwestern University Feinberg School of Medicine, \nChicago, IL, USA. Electronic address: EVanin@luriechildrens.org.\n(5)Molecular Pharmacology & Biological Chemistry, Northwestern University, \nFeinberg School of Medicine, Chicago, IL, USA. Electronic address: \nbula@northwestern.edu.\n(6)Molecular Pharmacology & Biological Chemistry, Northwestern University, \nFeinberg School of Medicine, Chicago, IL, USA. Electronic address: \na-belmadni@northwestern.edu.\n(7)Division of Pediatric Neurosurgery, Ann & Robert H Lurie Children's Hospital \nof Chicago Research Center, Ann & Robert H Lurie Children's Hospital of Chicago, \nNorthwestern University Feinberg School of Medicine, Chicago, IL, USA; Falk \nBrain Tumor Center, Ann & Robert H Lurie Children's Hospital of Chicago Research \nCenter, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern \nUniversity Feinberg School of Medicine, Chicago, IL, USA. Electronic address: \ngxi@luriechildrens.org.\n(8)Developmental Biology Program, Ann & Robert H Lurie Children's Hospital of \nChicago Research Center, Northwestern University, Feinberg School of Medicine, \nChicago, IL, USA. Electronic address: v-galat@northwestern.edu.\n(9)Microscopy and Imaging Facility, Ann & Robert H. Lurie Children's Hospital of \nChicago Research Center, Chicago, IL, USA. Electronic address: \nwgoossens@luriechildrens.org.\n(10)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA. Electronic address: r-seftor@northwestern.edu.\n(11)Division of Pediatric Neurosurgery, Ann & Robert H Lurie Children's Hospital \nof Chicago Research Center, Ann & Robert H Lurie Children's Hospital of Chicago, \nNorthwestern University Feinberg School of Medicine, Chicago, IL, USA; Falk \nBrain Tumor Center, Ann & Robert H Lurie Children's Hospital of Chicago Research \nCenter, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern \nUniversity Feinberg School of Medicine, Chicago, IL, USA. Electronic address: \nttomita@luriechildrens.org.\n(12)Division of Hematology/Oncology, Department of Pediatrics, Northwestern \nUniversity, Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA. Electronic address: j-crispino@northwestern.edu.\n(13)Molecular Pharmacology & Biological Chemistry, Northwestern University, \nFeinberg School of Medicine, Chicago, IL, USA. Electronic address: \nr-miller10@northwestern.edu.\n(14)Neurobiology Program, Ann & Robert H. Lurie Children's Hospital of Chicago \nResearch Center, Northwestern University, Feinberg School of Medicine, Chicago, \nIL, USA. Electronic address: m-bohn@northwestern.edu.\n(15)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, \nFeinberg School of Medicine, Northwestern University, Chicago, IL, USA. \nElectronic address: m-hendrix@northwestern.edu.\n(16)Cancer Biology and Epigenomics Program, Ann & Robert H Lurie Children's \nHospital of Chicago Research Center, Department of Pediatrics, Robert H. Lurie \nComprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA; Division of Hematology/Oncology, Department of \nPediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL, \nUSA; Falk Brain Tumor Center, Ann & Robert H Lurie Children's Hospital of \nChicago Research Center, Ann & Robert H Lurie Children's Hospital of Chicago, \nNorthwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. \nLurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern \nUniversity, Chicago, IL, USA. Electronic address: m-soares@northwestern.edu.",
"Embryonic stem cells (ESCs) are unique in that they have the capacity to \ndifferentiate into all of the cell types in the body. We know a lot about the \ncomplex transcriptional control circuits that maintain the naive pluripotent \nstate under self-renewing conditions but comparatively less about how cells exit \nfrom this state in response to differentiation stimuli. Here, we examined the \nrole of Otx2 in this process in mouse ESCs and demonstrate that it plays a \nleading role in remodeling the gene regulatory networks as cells exit from \nground state pluripotency. Otx2 drives enhancer activation through affecting \nchromatin marks and the activity of associated genes. Mechanistically, Oct4 is \nrequired for Otx2 expression, and reciprocally, Otx2 is required for efficient \nOct4 recruitment to many enhancer regions. Therefore, the Oct4-Otx2 regulatory \naxis actively establishes a new regulatory chromatin landscape during the early \nevents that accompany exit from ground state pluripotency.",
"Self-renewal and pluripotency in human embryonic stem cells (hESCs) depends upon \nthe function of a remarkably small number of master transcription factors (TFs) \nthat include OCT4, SOX2, and NANOG. Endogenous factors that regulate and \nmaintain the expression of master TFs in hESCs remain largely unknown and/or \nuncharacterized. Here, we use a genome-wide, proteomics approach to identify \nproteins associated with the OCT4 enhancer. We identify known OCT4 regulators, \nplus a subset of potential regulators including a zinc finger protein, ZNF207, \nthat plays diverse roles during development. In hESCs, ZNF207 partners with \nmaster pluripotency TFs to govern self-renewal and pluripotency while \nsimultaneously controlling commitment of cells towards ectoderm through direct \nregulation of neuronal TFs, including OTX2. The distinct roles of ZNF207 during \ndifferentiation occur via isoform switching. Thus, a distinct isoform of ZNF207 \nfunctions in hESCs at the nexus that balances pluripotency and differentiation \nto ectoderm."
] | nan |
5a67b2f7b750ff445500000f | [
25966437,
2724231,
25315465,
22855114,
23184140,
3585870,
3056562,
25134295,
23266205
] | train | Which type of urinary incontinence is diagnosed with the Q tip test? | factoid | Stress urinary incontinence is diagnosed with the Q tip test. The test evaluates urethral mobility. | stress urinary incontinence | [
"OBJECTIVE: To compare the change of urethral mobility after midurethral sling \nprocedures in stress urinary incontinence with hypermobile urethra and assess \nthese findings with surgical outcomes.\nSTUDY DESIGN: 141 women who agreed to undergo midurethral sling operations due \nto stress urinary incontinence with hypermobile urethra were enrolled in this \nnon-randomized prospective observational study. Preoperatively, urethral \nmobility was measured by Q tip test. All women were asked to complete Urogenital \nDistress Inventory Short Form (UDI-6) and Incontinence Impact Questionnaire \nShort Form (IIQ-7) to assess the quality of life. Six months postoperatively, Q \ntip test and quality of life assessment were repeated. The primary surgical \noutcomes were classified as cure, improvement and failure. Transient urinary \nobstruction, de novo urgency, voiding dysfunction were secondary surgical \noutcomes.\nRESULTS: Of 141 women, 50 (35. 5%) women underwent TOT, 91 (64.5%) underwent \nTVT. In both TOT and TVT groups, postoperative Q tip test values, IIQ-7 and \nUDI-6 scores were statistically reduced when compared with preoperative values. \nPostoperative Q tip test value in TVT group was significantly smaller than in \nTOT group [25°(15-45°) and 20° (15-45°), respectively]. When we compared the \nQ-tip test value, IIQ-7 and UDI-6 scores changes, there were no statistically \nsignificant changes between the groups. Postoperative urethral mobility was more \nfrequent in TOT group than in TVT group (40% vs 23.1%, respectively). \nPostoperative primary and secondary outcomes were similar in both groups.\nCONCLUSIONS: Although midurethral slings decrease the urethtal hypermobility, \npostoperative mobility status of urethra does not effect surgical outcomes of \nmidurethral slings in women with preoperative urethral hypermobility.",
"Fifteen women with a clinical and urodynamic diagnosis of stress urinary \nincontinence had a negative Q-tip test (greater than or equal to 30 degrees \nQ-tip angle change on straining). All 15 had retropubic surgical procedures for \nstress incontinence in the form of a revised Pereyra procedure (n = 6) or Burch \nretropubic urethropexy (n = 9). Five of the nine patients undergoing the Burch \nprocedure (55%) and three of the six undergoing the Peyreya procedure (50%) \nfailed the procedure, for an overall failure rate of 53%. This rate was five \ntimes higher than that among women with stress urinary incontinence and a \npositive Q-tip test who underwent the same procedures (P less than .01). We \nconclude that women with stress urinary incontinence and no anatomic defect in \nthe support of the urethrovesical junction should not undergo retropubic \nprocedures because of their high failure rate. Other occlusive procedures, such \nas sling operations, should be considered for this group.",
"PURPOSE: To clarify the association between clinically defined simple stress \nurinary incontinence (SUI) symptoms and urodynamic SUI, we examined the \nrelationship between Valsalva leak point pressure (VLPP) as measured by the \nQ-tip test and Stamey grade in simple female SUI.\nMETHODS: Two hundred grade I or II female SUI patients with SUI symptom were \nexamined by reviewing medical history; physical examination; urethral mobility \nas assessed by Q-tip test; stress test; and cystometry, including VLPP \nmeasurement. On the basis of the VLPP, patients were classified into urethral \nhypermobility [UH, subdivided into anatomical incontinence (AI) and equivocal \nincontinence (EI)] or intrinsic sphincter deficiency groups for analysis of the \nrelationship between VLPP and Stamey grade and Q-tip angle.\nRESULTS: Seventy-eight patients were included, and the mean patient age was 54 ± \n7.5 years, mean SUI symptom duration 2.8 years (range 0.5-6 years), mean VLPP \n103.6 ± 18.4 cm H2O, and mean Q-tip angle 28.6° ± 7.2°. Fifty-three patients \nwere categorized as Stamey grade I, 25 as Stamey grade II, 51 as AI, and 27 as \nEI. VLPP was found to be negatively correlated with Q-tip angle (Rs = -0.798, Y \n= -0.313X + 60.95, P < 0.001), and classifications of VLPP and Stamey grade have \npositive correlation (χ (2) = 4.9130, P = 0.0267).\nCONCLUSIONS: In simple female SUI, VLPP is associated with the Q-tip angle and \nStamey grade, which may help to reduce some of urodynamic items.",
"INTRODUCTION AND HYPOTHESIS: The aim of the study was to exclude neurovascular \ndamage due to prosthetic mini-invasive surgery using transobturator tape (TOT) \nby pre- and postoperative electromyography (EMG) of the striated urethral \nsphincter and a color Doppler ultrasonography evaluation of clitoral blood flow.\nMETHODS: A total of 25 women affected by clinical stress urinary incontinence \n(SUI) were enrolled. After undergoing urodynamic assessment, pelvic organ \nprolapse quantification, urine culture, Q-tip test, and stress test, each \nsubject underwent color Doppler ultrasonography to record clitoral blood flow \nand EMG of the urethral sphincter with a needle electrode inserted through the \nmucosa into the muscle tissue before surgery. A single urogynecologist performed \nthe TOT surgical technique for the treatment of all patients. Urogynecologic \nexamination, EMG, and color Doppler ultrasound follow-up were performed at 1 and \n6 months after surgery.\nRESULTS: At the urogynecologic examination performed 1 and 6 months after the \nTOT approach the stress test was negative, urethral hypermobility was reduced, \nand sling exposure was not observed for each patient. There was no statistically \nsignificant difference in electromyographic values (p > 0.05) in both the \nfollow-ups with regard to baseline values. Pulsatility index (PI), resistance \nindex (RI), and peak systolic velocity (PSV) values increased during the first \nfollow-up (p < 0.01); PI and RI values increased during the second follow-up \nwith respect to baseline values (p < 0.01)\nCONCLUSIONS: TOT prosthesis surgery, avoiding denervation and devascularization \nof pelvic structures, does not damage the urethral sphincter.",
"OBJECTIVE: To compare the outcome of outside-in biological and synthetic \ntransobturator tape (TOT) operation, including subjective and objective success \nrates, urodynamics, and quality of life.\nMATERIALS AND METHODS: One hundred patients suffering from clinical and/or \nurodynamic stress urinary incontinence (SUI) were randomized into biological \nmaterial TOT (PELVILACE® TO) or synthetic material TOT (ALIGN®TO Urethral \nSupport System) groups. Preoperative and at 1 year postoperative \nurogynecological symptom assessment, 1-h pad test, 4-day bladder diary, stress \ntest, Q-tip test, and urodynamics were performed. For the evaluation of quality \nof life, the King's Health Questionnaire, Urogenital Distress Inventory-6, \nIncontinence Impact Questionnaire-7, and Prolapse Quality of Life were used.\nRESULTS: There was no significant difference between the two groups regarding \nobjective and subjective cure rates and quality of life. At 1-year follow-up, \nthe subjective cure rate was 68 % in the biological material TOT and 70 % in the \nsynthetic material TOT group. No perioperative complications developed. Groin \npain developed in 2 patients in the biological TOT group and 1 patient had \ndehiscence in the periurethral incision, which healed with local estrogen. Two \npatients had transient urinary retention in the synthetic TOT group, 1 patient \ndeveloped groin pain, and 1 patient had mesh erosion observed at the 1-year \nfollow-up.\nCONCLUSION: Transobturator tape with biological material in the management of \nSUI has a rate of success and patient satisfaction similar to those of synthetic \nmaterial at 1-year follow-up. Studies with longer follow-up and larger cohorts \nare necessary to evaluate possible autolysis and degradation of biological \nslings and a possible reduction in efficacy over time.",
"The Q-tip test was applied on 105 patients. Fifty-one had stress urinary \nincontinency (SUI), 28 had bladder instability by clinical and urodynamic \ncriteria, and 36 had mild or moderate pelvic relaxation without urinary \npathology. More than 90% of the patients with SUI and no previous surgery had a \npositive Q-tip test, with 90% test sensitivity in this group. More than \none-third of the patients with bladder instability and almost one-half of the \npatients with pelvic relaxation and no urinary incontinence had a positive Q-tip \ntest, for low test specificity. The Q-tip test is a simple clinical tool for \ndiagnosing pelvic relaxation, which at times leads to SUI. Almost all patients \nwith primary SUI have pelvic relaxation. The Q-tip test alone does not stand as \na diagnostic test. When it is positive, the diagnosis of genuine stress \nincontinence is possible although not absolute. A negative test should cause one \nto question the diagnosis of genuine stress incontinence, and sophisticated and \nmore expensive tests should be ordered before establishing a final diagnosis.",
"Thirty-two female patients with clinical and urodynamic findings of genuine \nstress urinary incontinence were evaluated before and 6 months after surgery for \nstress urinary incontinence. Twenty-nine control patients had identical \nevaluations before and 6 months after surgery which did not involve the \nurethrovesical junction. Twenty-four patients with primary bladder instability \nhad similar evaluations and served as a second control group. Anatomical \nlandmarks indicating support to the urethrovesical junction were evaluated by \nthe position of the urethra at the most dependent point in the bladder on \nstraining and the urethral descent on straining to beneath the posterior ramus \nof the symphysis pubis on bead chain cystography. The urethrovesical junction \ndrop on straining was evaluated by transrectal ultrasonography. Cystographic and \nultrasonographic tests for the position of the urethrovesical junction at the \nmost dependent position in the bladder during straining were very sensitive in \nwomen with stress urinary incontinence (94 and 87% respectively) but much less \nspecific (45 and 48% respectively). When evaluating anatomical support to the \nurethrovesical junction and its descent on straining, these tests were both \nhighly sensitive (97 and 94% respectively) and specific (76 and 96% \nrespectively) in women with genuine stress urinary incontinence. Simple clinical \ntests for support of the urethrovesical junction, such as the Q tip test, are \nnon-specific in patients with stress urinary incontinence. Transrectal \nultrasonography is a simple and quick out-patient procedure. The availability of \nultrasound equipment in most clinics and the high sensitivity and specificity of \nthe test make it an attractive and cost-effective alternative to X-ray \ncystography in the pre-operative evaluation of anatomical support to the \nurethrovesical junction.",
"PURPOSE: To assess the effectiveness of inside-out TVT-ABBREVO in the surgical \ntreatment of female stress urinary incontinence (SUI) with mean two-year \nfollow-up.\nMATERIALS AND METHODS: Fifty-six women underwent surgery for moderate-severe \nSUI. The technology used was the TVT-ABBREVO inside-out. Each woman at 12 and 24 \nmonths underwent postoperative evaluation by means of urodynamics, Q-tip test, \nCST, transperineal ultrasonography, and administration of \"King's Health \nQuestionnaire\" (KHQ).\nRESULTS: The mean age of the women was 57.03 +/- 11.1 years (range 42-75). \nPostoperative urodynamics (12 months follow-up) resulted to be normal in 43/56 \npatients (76.79%), in 10/56 (17.86%) cases resulted in a considerable \nimprovement of the symptomatology, and only 1/56 (1.78%) case had de novo \noveractive bladder (OAB), in 2/56 (3.57%) symptomatology unchanged. After \nadministration of the KHQ 43/56 cases (76.79%) had resolution of the \nsymptomatology, 10/56 cases (17.86%) improvement of the symptomatology, and no \nchange in 3/56 cases (5.36%).\nCONCLUSION: In the authors' experience, the TVT-ABBREVO resulted technically \nsimple. The TVT-ABBREVO procedure provides high objective and subjective \nlong-term efficacy, a clinically meaningful improvement in patient quality of \nlife, and an excellent safety profile.",
"OBJECTIVE: To evaluate the impact of a more limited paraurethral dissection, \navoidance of perforating the obturator membrane with scissors or guide, and a \nmore medial trajectory of the trocar in positioning the TVT-O device on stress \nurinary incontinence cure rates.\nSTUDY DESIGN: One hundred and ten patients were recruited for this randomized, \nsingle blind, multicenter, non-inferiority study, with a 1:1 ratio to undergo \nthe traditional (n=55) or the modified (n=55) technique. Preoperatively, \npatients underwent POP-Q staging, Q-tip test, challenge stress test and \nurodynamics, and completed the I-QoL, PISQ-12, and PGI-S questionnaires. During \nthe post-operative period, patients attributed a pain VAS score 1, 3, 6, 12 and \n24h after the procedure and were followed up at 12 months, undergoing the same \nbaseline evaluations. The primary outcome was the cure rate (absence of urine \nleaks at the challenge stress test or urodynamic testing) one year after the \nprocedure. The primary outcome was evaluated using a non-inferiority test.\nRESULTS: No differences were observed in cure rates (traditional technique 92.3% \nvs. modified technique 88.8% and non-inferiority P<0.05) and in questionnaire \nscores between the two groups. Post-operative pain was significantly lower in \nthe modified technique group at each time point assessed, with the exception of \n12h post-operatively. No differences between the two groups were observed in the \nnumber of analgesic vials administered.\nCONCLUSIONS: The modified technique does not seem to reduce the efficacy of \nTVT-O, but induces a reduction of post-operative pain."
] | ['https://meshb.nlm.nih.gov/record/ui?ui=D014549'] |
5e2f6353fbd6abf43b00002b | [
27060149
] | train | Which type of variants can be called by the VarDict algorithm? | list | VarDict is a novel and versatile variant caller for both DNA- and RNA-sequencing data. It simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on the fly for more accurate allele frequency estimation. | ['SNV', 'MNV', 'InDels', 'complex variants', 'structural variants'] | [
"Accurate variant calling in next generation sequencing (NGS) is critical to \nunderstand cancer genomes better. Here we present VarDict, a novel and versatile \nvariant caller for both DNA- and RNA-sequencing data. VarDict simultaneously \ncalls SNV, MNV, InDels, complex and structural variants, expanding the detected \ngenetic driver landscape of tumors. It performs local realignments on the fly \nfor more accurate allele frequency estimation. VarDict performance scales \nlinearly to sequencing depth, enabling ultra-deep sequencing used to explore \ntumor evolution or detect tumor DNA circulating in blood. In addition, VarDict \nperforms amplicon aware variant calling for polymerase chain reaction \n(PCR)-based targeted sequencing often used in diagnostic settings, and is able \nto detect PCR artifacts. Finally, VarDict also detects differences in somatic \nand loss of heterozygosity variants between paired samples. VarDict reprocessing \nof The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known \ndriver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than \npreviously published variant calls. We believe VarDict will greatly facilitate \napplication of NGS in clinical cancer research."
] | nan |
553babc0f321868558000007 | [
14598129,
20976394,
23937262,
9526919
] | train | Which types of bacterial microflora are associated with the progression of peri-implantitis? | list | Bacteria such as A. actinomycetemcomitans, P. gingivalis, T. forsythensis, T. denticola, P. intermedia and F. nucleatum are associated with the progression of peri-implantitis. | ['A. actinomycetemcomitans', 'P. gingivalis', 'T. denticola', 'T. forsythia', 'P. intermedia', 'F. nucleatum'] | [
"Many oral pathologies, such as dental caries, periodontal disease and \nperi-implantitis are plaque-related. Dental plaque is a microbial biofilm formed \nby organisms tightly bound to a solid substrate and each other by means of an \nexopolymer matrix. Bacteria exhibit different properties when contained within a \nbiofilm. Knowing the mechanisms controlling the formation and development of \nbiofilms can help to understand the emergence and progression of such \npathologies and to plan effective treatment. Most periodontal pathogens are \ncommon saprophytes of the oral cavity, expressing their virulence only in a \nsusceptible host or when some changes come about in the oral environment. \nPhysical, metabolic and physiological interactions may cause positive or \nnegative effects among the various microbiota present. Such mechanisms of \nantagonism/synergy select the bacterial population and alterations of its \ncomposition affect the balance with the host and may lead to pathology. The \neffectiveness of antimicrobial agents, as measured through in vitro tests, is \ndramatically reduced in vivo due to the properties of the microbial community: \nmature, intact biofilms are less sensitive to such agents, as the exopolymer \nmatrix, bacterial enzymes and slow growth rate hinder the action of \nchemotherapeutic agents. The present literature review aims to examine the most \nrepresentative studies, focusing on the characteristics of bacterial communities \nand the crucial shift from oral health to plaque-related diseases.",
"The search for the etiologic agents of periodontal diseases started in the \nGolden Era of medical bacteriology, when the etiologic agents of many bacterial \ninfections were isolated and characterized. After the initial enthusiasm in \nestablishing the infectious nature and the true agents of periodontal diseases, \nthis concept was virtually ignored for the next four decades. Until the early \n1970s treatment regimens based on the non-specific plaque hypothesis were \ndirected towards a non-specific reduction in plaque amount. Later, the specific \nplaque hypothesis established the role of some microorganisms such as A. \nactinomycetemcomitans, P. gingivalis, T. forsythensis, T. denticola, P. \nintermedia and F. nucleatum in different forms of periodontal diseases. It was \nrecently suggested that these suspected periodontal pathogens seem to not act \nalone and interactions between species, especially the balance between \npathogenic and beneficial species affect both progression of disease and \nresponse of tissues to periodontal therapy. Nowadays it is well established that \none of the goals of therapy is to control such periodontal pathogens. Among the \nmost commonly used therapies to treat periodontal infections are scaling and \nroot planing (SRP), supragingival plaque control and periodontal surgeries. Many \nstudies confirmed the reduction of \"red complex\" species by SRP, and apically \nrepositioned flap can lead to an additional beneficial effect in the subgingival \nmicrobiota by decreasing levels of \"red\" and \"orange complexes\" species. \nFurthermore, the level of plaque control maintained by the patients has been \nconsidered a crucial step in preventing recurrence of destructive periodontitis.",
"AIM: To analyze the microbial profile around teeth and implants following \nligature removal in experimental periodontitis and peri-implantitis in dogs.\nMATERIAL AND METHODS: Four implants with similar geometry and with two different \nsurface characteristics (implant A: turned/implant B: TiUnite; NobelBiocare AB) \nwere placed pairwise in the right side of the mandible 3 months after tooth \nextraction in five dogs. Experimental periodontitis and peri-implantitis were \ninitiated 3 months later by ligature placement around implants and mandibular \npremolars and plaque formation. The ligatures were removed after 10 weeks. \nMicrobial samples were obtained using paper points immediately after ligature \nremoval, at 10 and 25 weeks after ligature removal. The microbiological analysis \nwas performed by \"checkerboard\" DNA-DNA hybridization, including a panel of 16 \nbacterial species.\nRESULTS: The amount of bone loss that occurred during the period following \nligature removal was significantly larger at implants with a modified surface \nthan at implants with a turned surface and at teeth. The microbiological \nanalysis revealed that the total bacterial load increased during the period \nfollowing ligature removal and established an anaerobic Gram-negative \nmicroflora.\nCONCLUSION: It is suggested that the large variation in regard to the microbial \nprofiles makes interpretation of a correlation between disease progression and \nmicrobial profiles difficult.",
"This study examines the microbiota associated with the progression of \nexperimental peri-implantitis and periodontitis induced concurrently in \npartially edentulous adult monkeys. Root-form and plate-form implants with fixed \nprosthesis in place for at least 12 months and their corresponding opposite \nmolar teeth were ligated for 6 months. The microbiota in plaque around these \nligated dental implants and molars were studied at 0, 1, 2, 3, and 6 months \npost-ligation. Plaque samples were analyzed by dark-field microscopy and \nselective and non-selective culture. Putative periodontal pathogens were \ndetected as a major component of the microbiota cultured from plaque samples \nobtained from experimental peri-implantitis sites. Overall, the types and \nrelative proportions of putative periodontal pathogens in plaque associated with \nligature-induced peri-implantitis and ligature-induced periodontitis were \nsimilar. Only levels of anaerobic Actinomyces and spirochetes were significantly \ndifferent between both sites. Spirochete levels were significantly higher at \nperi-implantitis sites when compared with levels at periodontitis sites after 6 \nmonths, and spirochete levels increased significantly between 0 and 6 months \npost-ligation at implant sites. Levels of spirochetes correlated significantly \nwith probing depth and bone loss at peri-implantitis sites. Overall, Actinomyces \nlevels were higher at periodontitis sites. Porphyromonas species were not \ndetected continuously as part of the peri-implantitis microbiota. In conclusion, \nthis study finds that the microbiota associated with the progression of \nexperimental peri-implantitis and periodontitis occurring concurrently in \npartially edentulous mouths are similar."
] | ['http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D057873'] |
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] | train | Which types of cancer can be recognized and treated by the use of immunotherapy? | list | When normal cells turn into cancer cells, some of the antigens on their surface change. These cells, like many body cells, constantly shed bits of protein from their surface into the circulatory system. Often, tumor antigens are among the shed proteins.
These shed antigens prompt action from immune defenders, including cytotoxic T cells, natural killer cells, and macrophages. According to one theory, patrolling cells of the immune system provide continuous bodywide surveillance, catching and eliminating cells that undergo malignant transformation. Tumors develop when this immune surveillance breaks down or is overwhelmed.
A new approach to cancer therapy uses antibodies that have been specially made to recognize specific cancers such as Melanoma, Leukaemia, Lung Cancer, Colorectal Cancer, Breast Cancer, Head Cancer and Pancreatic Cancer. | ['Melanoma', 'Leukaemia', 'Lung Cancer', 'Colorectal Cancer', 'Breast Cancer', 'Head Cancer', 'Pancreatic Cancer', 'Prostate tumor'] | [
"Since the discovery of tumor-associated antigens (TAAs), researchers have tried \nto develop immune-based anti-cancer therapies. Thanks to their specificity, \nmonoclonal antibodies (mAbs) offer the major advantage to induce fewer side \neffects than those caused by non-specific conventional treatments (e.g., \nchemotherapy, radiotherapy). Passive immunotherapy by means of mAbs or cytokines \nhas proved efficacy in oncology and validated the use of immune-based agents as \npart of anti-cancer treatment options. The next step was to try to induce an \nactive immune protection aiming to boost own's host immune defense against TAAs. \nCancer vaccines are thus developed to specifically induce active immune \nprotection targeting only tumor cells while preserving normal tissues from a \nnon-specific toxicity. But, as most of TAAs are self antigens, an immune \ntolerance against them exists representing a barrier to effective vaccination \nagainst these oncoproteins. One promising approach to break this immune \ntolerance consists in the use of anti-idiotypic (anti-Id) mAbs, so called Ab2, \nas antigen surrogates. This vaccination strategy allows also immunization \nagainst non-proteic antigens (such as carbohydrates). In some clinical studies, \nanti-Id cancer vaccines indeed induced efficient humoral and/or cellular immune \nresponses associated with clinical benefit. This review article will focus on \nrecent achievements of anti-Id mAbs use as cancer vaccines in solid tumors.",
"The tumor microenvironment is a complex assortment of cells that includes a \nvariety of leukocytes. The overall effect of the microenvironment is to support \nthe growth of tumors and suppress immune responses. Immunotherapy is a highly \npromising form of cancer treatment, but its efficacy can be severely compromised \nby an immunosuppressive tumor microenvironment. Chemotherapy and radiation \ntreatment can mediate tumor reduction through cytotoxic effects, but it is \nbecoming increasingly clear that these forms of treatment can be used to modify \nthe tumor microenvironment to liberate tumor antigens and decrease \nimmunosuppression. Chemotherapy and radiotherapy can be used to modulate the \ntumor microenvironment to enhance immunotherapy.",
"CD4+ T cells promote cytotoxic T lymphocyte (CTL)-mediated anticancer immune \nresponses. We have recently identified ideal tumor-associated antigen \n(TAA)-derived long peptides (LPs) that elicit not only TAA-specific TH1 \nresponse, but also CTLs, through cross-presentation. The LP-specific TH1 cell \nresponses were augmented in cancer patients vaccinated with CTL epitopes. Our \nfindings support the clinical application of LP-based immunotherapy.",
"New York esophageal squamous cell carcinoma-1 (NY-ESO-1), a cancer testis \nantigen, is an ideal target for adoptive cell transfer immunotherapy. Evidence \nfrom several clinical trials in melanoma and other malignancies shows the \npotential value of targeting the NY-ESO-1 antigen in immune-based therapy of \nmetastatic tumors. However, the incidence of NY-ESO-1 expression in metastatic \nmelanoma is unknown, and thus, it is unclear how many patients might benefit \nfrom this therapy. In this study, we analyzed NY-ESO-1 expression in 222 \nmelanoma specimens, including 16 primary and 206 metastatic tumors. Our results \nsupport previous findings showing higher expression of NY-ESO-1 in metastatic \n(58/206; 28.2%) versus primary (0/16) tumors. In addition, our results show that \nthe epithelioid subtype of melanoma has the highest incidence of NY-ESO-1 \nexpression. These findings provide evidence of the value of this specific \nadoptive cell transfer therapy for the treatment of metastatic melanoma.",
"The superiority of dendritic cells (DCs) as antigen-presenting cells has been \nexploited in numerous clinical trials, where generally monocyte-derived DCs \n(Mo-DCs) are injected to induce immunity in patients with cancer or infectious \ndiseases. Despite promising expansion of antigen-specific T cells, the clinical \nresponses following vaccination have been limited, indicating that further \nimprovements of DC vaccine potency are necessary. Pre-clinical studies suggest \nthat vaccination with combination of primary DC subsets, such as myeloid and \nplasmacytoid blood DCs (mDCs and pDCs, respectively), may result in stronger \nclinical responses. However, it is a challenge to obtain high enough numbers of \nprimary DCs for immunotherapy, since their frequency in blood is very low. We \ntherefore explored the possibility to generate them from hematopoietic \nprogenitor cells (HPCs). Here, we show that by inhibiting the aryl hydrocarbon \nreceptor with its antagonist StemRegenin 1 (SR1), clinical-scale numbers of \nfunctional BDCA2(+)BDCA4(+) pDCs, BDCA1(+) mDCs, and BDCA3(+)DNGR1(+) mDCs can \nbe efficiently generated from human CD34(+) HPCs. The ex vivo-generated DCs were \nphenotypically and functionally comparable to peripheral blood DCs. They \nsecreted high levels of pro-inflammatory cytokines such as interferon (IFN)-α, \ninterleukin (IL)-12, and tumor necrosis factor (TNF)-α and upregulated \nco-stimulatory molecules and maturation markers following stimulation with \nToll-like receptor (TLR) ligands. Further, they induced potent allogeneic T-cell \nresponses and activated antigen-experienced T cells. These findings demonstrate \nthat SR1 can be exploited to generate high numbers of functional pDCs and mDCs \nfrom CD34(+) HPCs, providing an alternative option to Mo-DCs for immunotherapy \nof patients with cancer or infections.",
"BACKGROUND: Post-autologous stem cell transplantation (ASCT) consolidation and \nmaintenance therapies in multiple myeloma (MM) have recently been the central \nfocus of studies. However, there have been no reports of Japanese patients with \nMM treated with post-ASCT consolidation/maintenance therapies.\nPATIENTS AND METHODS: We retrospectively evaluated eight Japanese patients with \nnewly-diagnosed symptomatic MM who received ASCT after high-dose melphalan, and \nthree to four courses of bortezomib-plus-dexamethasone and two courses of \nlenalidomide-plus-dexamethasone followed by maintenance lenalidomide for 6-24 \nmonths.\nRESULTS: Four patients achieved complete response (CR) after ASCT, and five \npatients (63%) achieved stringent CR after the consolidation and maintenance \ntherapy; two out of these five were in molecular CR. At the median follow-up of \n38 months, all patients were alive and only one patient had disease progression \nfollowing post-ASCT therapy.\nCONCLUSION: Post-ASCT consolidation and maintenance therapy using lenalidomide \nmay be effective in the treatment of Japanese patients with MM.",
"The 6th annual Cancer Vaccines and Immunotherapy Colloquium at Walker's Cay was \nheld under the auspices of the Albert B. Sabin Vaccine Institute on March 10-13, \n2004. The Colloquium consisted of a select group of 34 scientists representing \nacademia, biotechnology and pharmaceutical industry. The main goal of this \ngathering was to promote in a peaceful and comfortable environment exchanges \nbetween basic and clinical science. The secondary benefit was to inspire novel \nbench to bedside ventures and at the same time provide feed back about promising \nand/or disappointing clinical results that could help re-frame some scientific \nquestion or guide the design of future trials. Several topics were covered that \nincluded tumor antigen discovery and validation, platforms for vaccine \ndevelopment, tolerance, immune suppression and tumor escape mechanisms, adoptive \nT cell therapy and dendritic cell-based therapies, clinical trials and \nassessment of response. Here we report salient points raised by speakers or by \nthe audience during animated discussion that followed each individual \npresentation.",
"The ErbB network is dysregulated in many solid tumors. To exploit this, we have \ndeveloped a chimeric Ag receptor (CAR) named T1E28z that targets several \npathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric \ncytokine receptor named 4αβ (combination termed T4), enabling the selective \nexpansion of engineered T cells using IL-4. Human T4(+) T cells exhibit \nantitumor activity against several ErbB(+) cancer types. However, ErbB receptors \nare also expressed in several healthy tissues, raising concerns about toxic \npotential. In this study, we have evaluated safety of T4 immunotherapy in vivo \nusing a SCID beige mouse model. We show that the human T1E28z CAR efficiently \nrecognizes mouse ErbB(+) cells, rendering this species suitable to evaluate \npreclinical toxicity. Administration of T4(+) T cells using the i.v. or \nintratumoral routes achieves partial tumor regression without clinical or \nhistopathologic toxicity. In contrast, when delivered i.p., tumor reduction is \naccompanied by dose-dependent side effects. Toxicity mediated by T4(+) T cells \nresults from target recognition in both tumor and healthy tissues, leading to \nrelease of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme \ncases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by \nprior macrophage depletion, consistent with clinical data that implicate IL-6 in \nthis pathogenic event. These data demonstrate that CAR-induced cytokine release \nsyndrome can be modeled in mice that express target Ag in an appropriate \ndistribution. Furthermore, our findings argue that ErbB-retargeted T cells can \nachieve therapeutic benefit in the absence of unacceptable toxicity, providing \nthat route of administration and dose are carefully optimized.",
"Parathyroid hormone-related protein (PTHrP) is a key factor in the development \nof bone metastases, which are a major barrier in treating prostate cancer \npatients. In this study, we attempted to identify PTHrP-derived peptides \nimmunogenic in human histocompatibility leukocyte antigen (HLA)-A24(+) prostate \ncancer patients. Among four different PTHrP peptides carrying the HLA-A24 \nbinding motif, both the PTHrP(36-44) and PTHrP(102-111) peptides efficiently \ninduced peptide-specific cytotoxic T lymphocytes from peripheral blood \nmononuclear cells (PBMCs) of HLA-A24(+) prostate cancer patients. \nPeptide-stimulated PBMCs showed cytotoxicity against prostate cancer cells in an \nHLA-A24-restricted manner. Experiments using antibodies and cold inhibition \ntargets confirmed that their cytotoxicity was dependent on PTHrP \npeptide-specific and CD8(+) T cells. Immunoglobulin G reactive to the \nPTHrP(102-111) or PTHrP(110-119) peptide was frequently detected in the plasma \nof prostate cancer patients, suggesting that the PTHrP(102-111) peptide is able \nto elicit cellular and humoral immune responses in cancer patients. These \nresults indicate that the PTHrP could be a promising target molecule for \nspecific immunotherapy of HLA-A24(+) prostate cancer patients with metastases.",
"Regulatory T cells (Treg) play a key role in maintaining the balance of immune \nresponses in human health and in disease. Treg come in many flavors and can \nutilize a variety of mechanisms to modulate immune responses. In cancer, \ninducible (i) or adaptive Treg expand, accumulate in tissues and the peripheral \nblood of patients, and represent a functionally prominent component of CD4+ T \nlymphocytes. Phenotypically and functionally, iTreg are distinct from natural \n(n) Treg. A subset of iTreg expressing ectonucleotidases, CD39 and CD73, is able \nto hydrolyze ATP to 5'-AMP and adenosine (ADO) and thus mediate suppression of \nthose immune cells which express ADO receptors. iTeg can also produce \nprostaglandin E2 (PGE2). These iTreg, expanding in response to tumor antigens \nand cytokines such as TGF-β or IL-10, are presumably responsible for the \nsuppression of anti-tumor immune responses and for successful tumor escape. On \nthe other hand, in cancers associated with prominent inflammatory infiltrates, \ne.g., colorectal carcinoma or certain types of breast cancer, iTreg \ndown-regulate excessive inflammation by producing ADO and/or PGE2 and protect \nthe host from tissue injury and tumor development. Thus, iTreg utilizing the \nsame adenosine pathway play a key but dual role in cancer, and their plasticity \nis controlled and driven by the microenvironment. Thus, monitoring for the \nfrequency and functions of iTreg rather than nTreg is important in cancer. In \naddition, elimination of iTreg by various available strategies prior to \nimmunotherapies may not be beneficial in all cases and needs to be undertaken \nwith caution.",
"Twenty-five patients with metastatic melanoma were treated with a therapeutic \nvaccine (\"theraccine\") consisting of allogeneic melanoma lysates and a novel \nadjuvant, DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT). Each patient \nreceived 200 antigenic units (20 x 10(6) tumor cell equivalents) subcutaneously \non weeks 1, 2, 3, 4, and 6. Clinical responses included one complete remission, \nthree partial remissions, and a long-term (17-month) stability. Two other \npatients had mixed responses, with partial remissions of numerous subcutaneous \nnodules. Sites of responsive disease included primarily the skin, but ileal, \nbreast, and a liver metastasis also responded. Removal of residual lesions in \npatients with partial remissions, whose other lesions had disappeared during \ntreatment, led to long disease-free survivals. The median duration of remission \nwas 17 months, with four of the five responders alive for at least 24 months \nafter treatment. An increase in precursors of cytolytic T cells (CTLs) \ncorrelated with clinical outcome, when complete, partial, and mixed responses \nand long-term stability were considered. The CTLs recognized melanoma-associated \nantigens on many cell lines, but not other types of tumor or normal lymphocytes. \nSkin-test reactivity to melanoma antigens and serum antibodies against the \nmelanoma cells was unrelated to clinical response. Toxicity was minimal, \nrestricted largely to minor soreness at the site of injection. Only five \npatients, four of whom were treated with repeated courses, developed severe \ngranulomas. These results confirm that active-specific immunization with \nallogeneic lysates of melanoma administered with the adjuvant DETOX can induce \nimmunity to melanoma, and can induce regressions of disease in a proportion of \npatients with metastatic disease with little toxicity.",
"Dendritic cells (DCs) occupy a privileged position at the interface between \ninnate and adaptive immunity, orchestrating a large panel of responses to both \nphysiological and pathological cues. In particular, whereas the presentation of \nantigens by immature DCs generally results in the development of immunological \ntolerance, mature DCs are capable of priming robust, and hence therapeutically \nrelevant, adaptive immune responses. In line with this notion, functional \ndefects in the DC compartment have been shown to etiologically contribute to \npathological conditions including (but perhaps not limited to) infectious \ndiseases, allergic and autoimmune disorders, graft rejection and cancer. Thus, \nthe possibility of harnessing the elevated immunological potential of DCs for \nanticancer therapy has attracted considerable interest from both researchers and \nclinicians over the last decade. Alongside, several methods have been developed \nnot only to isolate DCs from cancer patients, expand them, load them with \ntumor-associated antigens and hence generate highly immunogenic clinical grade \ninfusion products, but also to directly target DCs in vivo. This intense \nexperimental effort has culminated in 2010 with the approval by the US FDA of a \nDC-based preparation (sipuleucel-T, Provenge®) for the treatment of asymptomatic \nor minimally symptomatic metastatic castration-refractory prostate cancer. As an \nupdate to the latest Trial Watch dealing with this exciting field of research \n(October 2012), here we summarize recent advances in DC-based anticancer \nregimens, covering both high-impact studies that have been published during the \nlast 13 mo and clinical trials that have been launched in the same period to \nassess the antineoplastic potential of this variant of cellular immunotherapy.",
"Transgenic rodent models of prostate cancer have served as valuable preclinical \nmodels to evaluate novel treatments and understand malignant disease \nprogression. In particular, a transgenic rat autochthonous model of prostate \ncancer using the SV40 large T antigen expressed under a prostate-specific \nprobasin promoter was previously developed as a model of androgen-dependent \nprostate cancer (TRAP). In the current report, we backcrossed this strain to the \nLewis strain, an inbred rat strain better characterized for immunological \nanalyses. We demonstrate that Lewis transgenic rats (Lew-TRAP) developed \nprostate adenocarcinomas with 100% penetrance by 25 weeks of age. Tumors were \npredominantly androgen-dependent, as castration prevented tumor growth in the \nmajority of animals. Finally, we demonstrate that Lew-TRAP rats could be \nimmunized with a DNA vaccine encoding a human prostate tumor antigen (prostatic \nacid phosphatase) with the development of Lewis strain-specific T-cell \nresponses. We propose that this Lew-TRAP strain, and prostate tumor cell lines \nderived from this strain, can be used as a future prostate cancer immunotherapy \nmodel.",
"Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and \nsarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung \ncancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma in \nchildren and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma \nand other soft tissue sarcomas in adults. Since GD2 expression in normal tissues \nis restricted to the brain, which is inaccessible to circulating antibodies, and \nin selected peripheral nerves and melanocytes, it was deemed a suitable target \nfor systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested \nin clinical trials for neuroblastoma for over the past two decades, with proven \nsafety and efficacy. The main limitations have been acute pain toxicity \nassociated with GD2 expression on peripheral nerve fibers and the inability of \nantibodies to treat bulky tumor. Several strategies have been developed to \nreduce pain toxicity, including bypassing complement activation, using blocking \nantibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on \nperipheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal \nantibodies and fragments have been engineered into immunocytokines, \nimmunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted \nnanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen \nreceptors. The challenges of these approaches will be reviewed to build a \nperspective for next generation anti-GD2 therapeutics in cancer therapy.",
"The programmed death-1 (PD-1) pathway is important in the maintenance of \nperipheral tolerance and homeostasis through suppression of T cell receptor \nsignaling. As such, it is employed by many tumors as a means of immune escape. \nWe have investigated the role of this pathway in human ovarian cancer (OC) to \nassess its potential role as a diagnostic and/or prognostic marker and \ntherapeutic target, following recent clinical trial success of antibody therapy \ndirected at this pathway. We show programmed death ligand-1 (PD-L1) expression \non monocytes in the ascites and blood of patients with malignant OC is \nstrikingly higher than those with benign/borderline disease, with no overlap in \nthe values between these groups. We characterize the regulation of this molecule \nand show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T \ncells present in the ascites and blood showed a correlation of PD-1 expression \nwith malignant tumors versus benign/borderline, in a similar manner to PD-L1 \nexpression on monocytes. Finally, we demonstrate functional links between PD-L1 \nexpression on monocytes and OC tumor cells with suppression of T cell responses. \nOverall, we present data based on samples obtained from women with ovarian \ncancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker \nin OC, as well as a viable target for use with PD-1/PD-L1-directed antibody \nimmunotherapy.",
"Cancer testis (CT) antigens are attractive targets for cancer immunotherapy \nbecause their expression is restricted in normal germ line tissues but \nfrequently detected in variety of tumors. OY-TES-1 is identified as a member of \nCT antigens. Current knowledge about OY-TES-1 expression in colorectal cancer \n(CRC) is solely based on mRNA analysis. None of previous researches has studied \nOY-TES-1 at protein level. In this study, OY-TES-1 polyclonal antibody was \ngenerated. The expression of OY-TES-1 mRNA and protein was detected by RT-PCR \nand immunohistochemistry in 60 CRC and paired adjacent non-tumor tissues, 24 \ncolorectal adenoma and 3 normal colon tissues, respectively. Sera from 73 CRC \npatients were also tested for OY-TES-1 antibody by ELISA. Our results showed \nthat the frequency of OY-TES-1 mRNA expression was statistically higher in CRC \n(73.3%, 44/60) than that in adjacent non-tumor tissue (55.0%, 33/60) and \ncolorectal adenoma (45.8%, 11/24). For the first time, OY-TES-1 protein \nexpression was found in (43.3%, 26/60) of CRC tissues, but absent in any of \nadjacent non-tumor and colorectal adenoma tissues. No OY-TES-1 expression was \nfound in normal colon by either RT-PCR or immunohistochemistry. Furthermore, \nOY-TES-1 protein expression was correlated with tumor invasion stage (P=0.004) \nand histological grade (P=0.040). Anti-OY-TES-1 antibody was detected in (9.6%, \n7/73) of CRC patients' sera but not in 76 healthy donors. This finding \ndemonstrates that OY-TES-1 is frequently expressed in CRC and is able to induce \nhumoral immune response spontaneously in CRC patients, suggesting that it might \nbe a promising immunotherapy target for CRC.",
"Substantial progress has been made in the treatment of precursor B-cell acute \nlymphoblastic leukemia (B-ALL), but recurrent disease remains a leading cause of \ndeath in children due to cancer and outcomes for adults with B-ALL remain poor. \nRecently, complete clinical responses have been observed in small numbers of \npatients with B-ALL treated with adoptive immunotherapy using T cells \ngenetically engineered to express chimeric antigen receptors (CARs) targeting \nCD19, a cell surface molecule present in essentially all cases of B-ALL. \nPreclinical data suggest that CARs targeting CD22, another antigen present in \nthe majority of B-ALL cases, are similarly potent. Several clinical studies \nalready under way will soon more clearly define the rate of response to this \nnovel therapy in B-ALL. Further work is needed to identify optimal platforms for \nCAR-based adoptive immunotherapy for leukemia, to establish guidelines for \nmanaging toxicity, and to determine whether the remissions induced by this \napproach can be rendered durable.",
"High-dose (HD) IL-2 therapy in patients with cancer increases the general \npopulation of Tregs, which are positive for CD4, CD25, and the Treg-specific \nmarker Foxp3. It is unknown whether specific subsets of Tregs are activated and \nexpanded during HD IL-2 therapy or whether activation of any particular Treg \nsubset correlates with clinical outcome. Here, we evaluated Treg population \nsubsets that were induced in patients with melanoma following HD IL-2 therapy. \nWe identified a Treg population that was positive for CD4, CD25, Foxp3, and the \ninducible T cell costimulator (ICOS). This Treg population increased more than \nany other lymphocyte subset during HD IL-2 therapy and had an activated Treg \nphenotype, as indicated by high levels of CD39, CD73, and TGF-β. ICOS(+) Tregs \nwere the most proliferative lymphocyte population in the blood after IL-2 \ntherapy. Patients with melanoma with enhanced expansion of ICOS(+) Tregs in \nblood following the first cycle of HD IL-2 therapy had worse clinical outcomes \nthan patients with fewer ICOS(+) Tregs. However, there was no difference in \ntotal Treg expansion between HD IL-2 responders and nonresponders. These data \nsuggest that increased expansion of the ICOS(+) Treg population following the \nfirst cycle of HD IL-2 therapy may be predictive of clinical outcome.",
"Due to the low survival rates from invasive ovarian cancer, new effective \ntreatment modalities are urgently needed. Compelling evidence indicates that the \nimmune response against ovarian cancer may play an important role in controlling \nthis disease. We herein summarize multiple immune-based strategies that have \nbeen proposed and tested for potential therapeutic benefit against advanced \nstage ovarian cancer. We will examine the evidence for the premise that an \neffective therapeutic vaccine against ovarian cancer is useful not only for \ninducing remission of the disease but also for preventing disease relapse. We \nwill also highlight the questions and challenges in the development of ovarian \ncancer vaccines, and critically discuss the limitations of some of the existing \nimmunotherapeutic strategies. Finally, we will summarize our own experience on \nthe use of patient-specific tumor-derived heat shock protein-peptide complex for \nthe treatment of advanced ovarian cancer.",
"Dendritic cell (DC)-based vaccines with the use of various antigen loading \nmethods have been developed for cancer immunotherapy. Electroporation (EP) of a \nwhole tumor cell lysate into DCs was previously found to be more potent for \neliciting antigen-specific CD8 + T-cells compared to co-incubation of tumor cell \nlysates with DCs in vitro. In the present report, we studied the feasibility, \nsafety and antitumor effect in the clinical use of an EP-DC vaccine for the \nimmunotherapy of various types of human solid tumors. We successfully prepared \nan autologous tumor lysate-loaded EP-DC vaccine with high cell viability by the \nclosed-flow electroporation system. In the phase I clinical trial, mild adverse \nevents associated with the EP-DC vaccine were found during the treatment of \nadvanced or recurrent cancer, or during the adjuvant therapy of some types of \ncancer; no autoimmune responses were observed after treatment with the \nautologous tumor lysate-loaded EP-DC vaccines. For the antitumor effect of the \nEP-DC vaccine against the 41 various types of solid tumor, the overall response \nrate [complete remission (CR) + partial response (PR)] was 4.9% (2/41) and the \nclinical benefit rate [CR+ PR + long stable disease (SD)] was 31.7% (13/41). \nFurthermore, the delayed-type hypersensitivity (DTH) reactivity was positive in \nmost cases of long SD and the positive rate of DTH was 91.7% (11/12) for the \npatients with clinical benefit. In conclusion, the safety and feasibility of the \nEP-DC vaccine with autologous tumor lysates were confirmed, and it was found \nthat the antitumor effect might be associated with the immunological response \ninduced by the EP-DC vaccine for cancer immunotherapy.",
"Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of \nmalignancy. Via a broad stimulation of the immune system, PDAC activates both \nantitumor immune responses and immunosuppressive mechanisms. We propose that new \nimmunotherapeutic strategies for the management of PDAC should be designed to \nspecifically neutralize the immunosuppressive tumor microenvironment."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009369', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D006258', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D001943', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D019496', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D007167', 'http://www.disease-ontology.org/api/metadata/DOID:162', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016219', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016233'] |
5c580aff07647bbc4b00001a | [
29456181
] | train | Which ultraconserved element is associated with Embryonic Stem Cells (ESC) self-renewal? | factoid | Ultraconserved elements (UCEs) show the peculiar feature to retain extended perfect sequence identity among human, mouse, and rat genomes. Most of them are transcribed and represent a new family of long non-coding RNAs (lncRNAs), the transcribed UCEs (T-UCEs). Despite their involvement in human cancer, the physiological role of T-UCEs is still unknown. A lncRNA containing the uc.170+, named T-UCstem1, was identified with in vitro and in vivo evidence that it plays essential roles in embryonic stem cells (ESCs) by modulating cytoplasmic miRNA levels and preserving transcriptional dynamics. | 1 | [
"Author information:\n(1)Stem Cell Fate Laboratory, Institute of Genetics and Biophysics \"A. \nBuzzati-Traverso\", CNR, 80131 Naples, Italy; Institute of Genetics and \nBiophysics \"A. Buzzati-Traverso\", CNR, 80131 Naples, Italy.\n(2)Institute of Genetics and Biophysics \"A. Buzzati-Traverso\", CNR, 80131 \nNaples, Italy.\n(3)Biosystems Analysis, LTTA, Department of Morphology, Surgery and Experimental \nMedicine, University of Ferrara, 44121 Ferrara, Italy.\n(4)National Institute of Molecular Biology, \"Romeo ed Enrica Invernizzi\", 20122 \nMilan, Italy.\n(5)Animal Medicine, Production and Health Department, University of Padua, 35020 \nPadua, Italy.\n(6)Stem Cell Fate Laboratory, Institute of Genetics and Biophysics \"A. \nBuzzati-Traverso\", CNR, 80131 Naples, Italy; Institute of Genetics and \nBiophysics \"A. Buzzati-Traverso\", CNR, 80131 Naples, Italy. Electronic address: \ngabriella.minchiotti@igb.cnr.it.\n(7)Stem Cell Fate Laboratory, Institute of Genetics and Biophysics \"A. \nBuzzati-Traverso\", CNR, 80131 Naples, Italy; Institute of Genetics and \nBiophysics \"A. Buzzati-Traverso\", CNR, 80131 Naples, Italy. Electronic address: \nannalisa.fico@igb.cnr.it."
] | nan |
53592c1e9a4572de6f000002 | [
9471429,
18726925,
16912493,
18461550,
19416569
] | train | Which value of nuchal translucency thickness is set as the threshold for high-risk for Down Syndrome? | factoid | NT is physiological for a measurement < 3 mm but the incidence of chromosomal abnormalities (essentially trisomies 21, 18 and 13) increases when NT > or = 3 mm. As women aged, this upper NT threshold value changed according to gestational age. In women aged 35 to 37 years, combined prenatal screening was always positive when NT exceeded 2.8 mm, 3.0 mm, and 3.4 mm at 11, 12, and 13 weeks of gestation, respectively. | 3 | [
"The purpose of the present literature review is to assess the screening value of \ntrisomy 21 by measurement of fetal nuchal translucency (NT) thickness in the \nfirst trimester. NT is a subcutaneous translucency between the skin and the soft \ntissues overlying the cervical spine, which disappears in the second trimester. \nUltrasound examination was used to image a sagittal section of the fetus to \nmeasure the maximum thickness of the subcutaneous translucency. NT is \nphysiological for a measurement < 3 mm but the incidence of chromosomal \nabnormalities (essentially trisomies 21, 18 and 13) increases when NT > or = 3 \nmm. Differential diagnoses include cystic hygroma and fetal hydrops. For \nscreening purposes, a cut-off threshold value of > or = 3 mm, with a \nstandardized technique, gave a sensitivity > or = 50%, a false positive rate < \n5% and a positive predictive value > 1%. In the chromosomally normal group, \nprognosis was good, but incidence of structural defects and fetal loss \nincreased, with a sharp rise in these complications for fetal translucency \nthickness > or = 5 mm.",
"OBJECTIVES: To derive a model and examine the performance of first-trimester \nscreening for trisomy 18 by maternal age, fetal nuchal translucency (NT) \nthickness, and maternal serum free beta-human chorionic gonadotropin (beta-hCG) \nand pregnancy-associated plasma protein-A (PAPP-A).\nMETHODS: Prospective combined screening for trisomy 21 was performed at 11 + 0 \nto 13 + 6 weeks in 56 893 singleton pregnancies, including 56 376 cases of \neuploid fetuses, 395 with trisomy 21 and 122 with trisomy 18. The measured free \nbeta-hCG and PAPP-A were converted into a multiple of the median (MoM) and then \ninto likelihood ratios (LR). Similarly, the measured NT was transformed into LRs \nusing the mixture model of NT distributions. In each case the LRs for NT and the \nbiochemical markers were multiplied by the age and gestation-related risk to \nderive the risk for trisomy 21 and trisomy 18. Detection rates (DRs) and \nfalse-positive rates (FPRs) were calculated by taking the proportions with risks \nabove a given risk threshold.\nRESULTS: In screening with the algorithm for trisomy 21, at a FPR of 3%, the \nestimated DRs of trisomies 21 and 18 were 89% and 82%, respectively. The use of \nan algorithm for trisomy 18 identified 93% of affected fetuses at a FPR of 0.2%. \nWhen the algorithm for trisomy 21 was used and screen positivity was fixed at a \nFPR of 3%, and in addition the algorithm for trisomy 18 was used and screen \npositivity was fixed at a FPR of 0.2%, the overall FPR was 3.1% and the DRs of \ntrisomies 21 and 18 were 90% and 97%, respectively.\nCONCLUSIONS: A beneficial side effect of first-trimester combined screening for \ntrisomy 21 is the detection of a high proportion of fetuses with trisomy 18. If \nan algorithm for trisomy 18 in addition to the one for trisomy 21 is used, more \nthan 95% of trisomy 18 fetuses can be detected with a minor increase of 0.1% in \nthe overall FPR.",
"OBJECTIVES: The purpose of this study is to assess the feasibility of foetal \nnasal bone (NB) measurement during the first trimester of pregnancy, and to \nexamine the contribution of this measurement to the prenatal screening for Down \nsyndrome following the definition of NB threshold using ROC curves in an \nunselected population.\nMETHODS: This prospective study was carried out at our centre SIHCUS-CMCO \n(reference centre) from January 2002 to December 2004 on a total of 2,044 \npregnant outpatients at gestational weeks 11-14. Only 1260 singleton foetuses \nwere used for statistical analysis. In the 784 other patients, we were unable to \nobtain a correct image allowing a reproducible measurement. NB was measured \nduring the same session as nuchal translucency (NT) measurement. Ten trained \nsonographers took part in the study. Correlation index was evaluated to shed \nlight on a link between interest variables and NB. Screening values of NB \nmeasurement in T 21 were also calculated with NB measurement according to \ncrown-rump length, and expressed as the best threshold of multiple of the median \ndetermined by ROC curve. Screening values of genetic ultrasound were then \nevaluated by adding NB measurement to maternal age and NT measurement.\nRESULTS: Two thousand and forty-four patients were included. We indexed 30 cases \nof T 21, 14 cases of Trisomy 18, 10 cases of Trisomy 13 and 25 cases of other \nkaryotype abnormalities. Feasibility of measurement was 62% of all cases. We \nobserved a significant relation between NB and NT (p = 0.001 ), as well as \nbetween NB and crown-rump-length (p < 0.0001 ). However, size of NB was not \ncorrelated to maternal ethnic group (p = 0.314). At 0.6 multiple of the median \nthresholds, screening values of NB measurement in T 21 were: sensibility 32%, \nfalse positive rate 10%, positive predictive value 13.6%, and negative \npredictive value 96.9%. The likelihood ratio for T 21 in case of NB < or = 0.6 \nmultiple of the median was 4.4 (2.0-9.4). Screening values for maternal age and \nNT measurement were: sensitivity 88%, false positive rate 23%,positive \npredictive value 9.7%, and negative predictive value 99.6%. Inclusion of NB \nmeasurement increased sensitivity to 100%, positive predictive value to 13.6%, \nand negative predictive value to 100%, and decreased false positive rate to 5%.\nCONCLUSION: NB measurement seemed to be a great sonographic marker for T 21. \nHowever, its low feasibility made it inadequate for routine settings in first \ntrimester T 21 screening in an unselected population. Statistical independence \nwith NT thickness needed to be further evaluated.",
"OBJECTIVES: To derive a model and examine the performance of first-trimester \ncombined screening by maternal age, fetal nuchal translucency (NT) thickness and \nmaternal serum free beta-human chorionic gonadotropin (beta-hCG) and \npregnancy-associated plasma protein-A (PAPP-A).\nMETHODS: Prospective combined screening for trisomy 21 was carried out at 11 + 0 \nto 13 + 6 weeks in 56,771 singleton pregnancies, including 56,376 cases with a \nnormal karyotype or delivery of a phenotypically normal baby (unaffected group) \nand 395 cases with trisomy 21. The blood test and ultrasound scan were carried \nout in the same visit. In each case the maternal age-related risk for trisomy 21 \nat term was calculated and adjusted according to the gestational age at the time \nof screening to derive the a-priori risk. The measured NT was transformed into a \nlikelihood ratio using the mixture model of NT distributions. The measured free \nbeta-hCG and PAPP-A were converted into a multiple of the median (MoM) for \ngestational age, adjusted for maternal weight, ethnicity, smoking status, method \nof conception and parity, and a likelihood ratio was subsequently calculated. \nThe likelihood ratios for NT and for the biochemical markers were multiplied by \nthe a-priori risk to derive the patient-specific risk. Detection rates and \nfalse-positive rates were calculated by taking the proportions with risks above \na given risk threshold after adjustment for maternal age according to the \ndistribution of pregnancies in England and Wales in 2000-2002. These \nstandardized rates were compared with detection and false-positive rates \nestimated using Monte Carlo methods to sample from the modeled Gaussian \ndistributions.\nRESULTS: The performance of screening based on the model was in good agreement \nwith that observed in our population. In a strategy for first-trimester combined \nscreening where the blood test and scan are carried out in the same visit it was \nestimated that, for false-positive rates of 3% and 5%, the detection rates were \n92% and 94%, respectively, at 11 weeks, 85% and 90% at 12 weeks, and 79% and 83% \nat 13 weeks. In an alternative strategy, with the blood taken at 10 weeks and \nthe measurement of NT performed at 12 weeks, the estimated detection rates were \n94% and 96% for false-positive rates of 3% and 5%, respectively.\nCONCLUSIONS: The aim of the first-trimester scan is not just to screen for \ntrisomy 21 but also to diagnose an increasing number of fetal malformations. In \nthis respect the ability to visualize fetal anatomy is better at 12-13 weeks \nthan at 11 weeks. Consequently, the ideal gestation for combined testing in the \nsame visit would be 12 weeks. An alternative strategy, with the blood taken at \n10 weeks and the measurement of NT performed at 12 weeks, is associated with \nhigher detection rates of trisomy 21. However, the cost of two-stage screening \nwould be higher and, in addition, the potential advantage in terms of detection \nrate may be eroded by the likely increased non-compliance with the additional \nstep.",
"OBJECTIVE: To determine if nuchal translucency (NT) can be used as a first \ntrimester triage marker in prenatal screening for Down syndrome and trisomy 18.\nMETHODS: Data from first trimester prenatal screening in 77 443 women were \nstratified by maternal and gestational ages. They were then analyzed to identify \nNT thresholds above or below which only positive (high-risk) or negative \n(low-risk) results were reported by a first trimester prenatal screening test \ncombining PAPP-A, free beta-hCG and NT.\nRESULTS: Combined prenatal screening was always positive for Down syndrome when \nNT thickness exceeded 4.0 mm. As women aged, this upper NT threshold value \nchanged according to gestational age. In women aged 35 to 37 years, combined \nprenatal screening was always positive when NT exceeded 2.8 mm, 3.0 mm, and 3.4 \nmm at 11, 12, and 13 weeks of gestation, respectively. In women over 42 years of \nage, the upper threshold value for NT was 1.8 mm, 2.4 mm, and 2.7 mm at 11, 12, \nand 13 weeks of gestation, respectively. In women less than 35 years of age, we \nidentified lower threshold values below which combined prenatal screening for \nDown syndrome was always negative.\nCONCLUSION: In prenatal screening for Down syndrome and trisomy 18, it is \npossible to identify NT threshold values above which biochemical screening \nprovides no additional benefit. In pregnancies in which NT is above the \nestablished upper cut-offs, invasive prenatal screening can be offered without \ndelay."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004314', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018566', 'http://www.disease-ontology.org/api/metadata/DOID:14250', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D048208'] |
550e9d2cb305b40c5c000001 | [
25542499,
24557701,
23894342,
23175723,
20007090,
25194739,
24473180,
24798141
] | train | Which variables are included in the SPAN-100 score? | list | SPAN-100 score includes patient's age and NIH Stroke Scale score. SPAN-100 is used for prognostication of stroke patients. | ['Age', 'NIH Stroke Scale score'] | [
"BACKGROUND: Prognostic scales can be helpful for selecting patients for \nreperfusion treatment. This study aims to assess the prognostic ability of the \nrecently published SPAN-100 index in a large cohort of stroke patients treated \nwith intravenous thrombolysis (IV rtPA).\nMETHODS: Using data from the prospective registery of all reperfusion treatments \nadministered in Catalonia, we selected patients treated with IV rtPA alone \nbetween 2011 and 2012. The SPAN-100 index was calculated as the sum of age \n(years) and NIHSS score, and patients in the cohort were classified as SPAN-100 \npositive [≥ 100] or SPAN-100 negative [< 100]. We measured raw and adjusted \nrates of symptomatic intracerebral haemorrhage (SICH), mortality, and 3-month \nfunctional outcome (mRS 0-2) for each SPAN-100 category. Area under the ROC \ncurve was calculated to predict the main outcome measures.\nRESULTS: We studied 1685 rtPA-treated patients, of whom 1405 (83%) were SPAN-100 \nnegative. The SICH rates adjusted for sex, pre-stroke mRS, hypertension, \ndiabetes, dyslipidaemia, ischaemic heart disease, heart failure, atrial \nfibrillation, prior TIA/stroke and time to thrombolysis did not differ between \ngroups, but likelihood of functional independence (mRS 0-2) at 3 months was \nnearly 8 times higher in the SPAN-100 negative group than in the positive group. \nFurthermore, the 3-month mortality rate was 5 times higher in the SPAN-100 \npositive group. ROC curve analysis showed high specificities for predicting both \nfunctional independence and 3-month mortality for a cut-off point of 100.\nCONCLUSION: The SPAN-100 index is a simple and straightforward method that may \nbe useful for selecting candidates for rtPA treatment in doubtful cases, and for \ninforming patients and their relatives about likely outcomes.",
"BACKGROUND AND PURPOSE: Age and stroke severity are inversely correlated with \nthe odds of favorable outcome after ischemic stroke. A previously proposed score \nfor Stroke Prognostication Using Age and NIHSS Stroke Scale (SPAN) indicated \nthat SPAN-100-positive patients (ie, age + NIHSS score = 100 or more) do not \nbenefit from IV-tPA. If this finding holds true for endovascular therapy, this \nscore can impact patient selection for such interventions. This study \ninvestigated whether a score combining age and NIHSS score can improve patients' \nselection for endovascular stroke therapy.\nMATERIALS AND METHODS: The SPAN index was calculated for patients in the \nprospective Solitaire FR Thrombectomy for Acute Revascularization study: an \ninternational single-arm multicenter cohort for anterior circulation stroke \ntreatment by using the Solitaire FR. The proportion with favorable outcome \n(90-day mRS score ≤2) was compared between SPAN-100-positive versus-negative \npatients.\nRESULTS: Of the 202 patients enrolled, 196 had baseline NIHSS scores. Fifteen \n(7.7%) patients were SPAN-100-positive. There was no difference in the rate of \nsuccessful reperfusion (Thrombolysis In Cerebral Infarction 2b or 3) between \nSPAN-100-positive versus -negative groups (93.3% versus 82.8%, respectively; P = \n.3). Stroke SPAN-100-positive patients had a significantly lower proportion of \nfavorable clinical outcomes (26.7% versus 60.8% in SPAN-100-negative, P = .01). \nIn a multivariable analysis, SPAN-100-positive status was associated with lower \nodds of favorable outcome (OR, 0.3; 95% CI, 0.1-0.9; P = .04). A higher baseline \nAlberta Stroke Program Early CT Score and a short onset to revascularization \ntime also predicted favorable outcome in the multivariable analysis.\nCONCLUSIONS: A significantly lower proportion of patients with a positive \nSPAN-100 achieved favorable outcome in this cohort. SPAN-100 was an independent \npredictor of favorable outcome after adjusting for time to treatment and the \nextent of preintervention tissue damage according to the Alberta Stroke Program \nEarly CT Score.",
"BACKGROUND: To evaluate if plasma levels of midregional pro-adrenomedullin \n(MR-proADM) improve prediction of functional outcome in ischemic stroke.\nMETHODS: In 168 consecutive ischemic stroke patients, plasma levels of MR-proADM \nwere measured within 24 hours from symptom onset. Functional outcome was \nassessed by the modified Rankin Scale (mRS) at 90 days following stroke. \nLogistic regression, receiver operating characteristics (ROC) curve analysis, \nnet reclassification improvement (NRI), and Kaplan-Meier survival analysis were \napplied.\nRESULTS: Plasma MR-proADM levels were found significantly higher in patients \nwith unfavourable (mRS 3-6) compared to favourable (mRS 0-2) outcomes. MR-proADM \nlevels were entered into a predictive model including the patients' age, \nNational Institutes of Health Stroke Scale (NIHSS), and the use of \nrecanalization therapy. The area under the ROC curve did not increase \nsignificantly. However, category-free NRI of 0.577 (p<0.001) indicated a \nsignificant improvement in reclassification of patients. Furthermore, MR-proADM \nlevels significantly improved reclassification of patients in the prediction of \noutcome by the Stroke Prognostication using Age and NIHSS-100 (SPAN-100; \nNRI = 0.175; p = 0.04). Kaplan-Meier survival analysis showed a rising risk of \ndeath with increasing MR-proADM quintiles.\nCONCLUSIONS: Plasma MR-proADM levels improve prediction of functional outcome in \nischemic stroke when added to the patients' age, NIHSS on admission, and the use \nof recanalization therapy. Levels of MR-proADM in peripheral blood improve \nreclassification of patients when the SPAN-100 is used to predict the patients' \nfunctional outcome.",
"OBJECTIVES: Age and stroke severity are major determinants of stroke outcomes, \nbut systematically incorporating these prognosticators in the routine practice \nof acute ischemic stroke can be challenging. We evaluated the effect of an index \ncombining age and stroke severity on response to IV tissue plasminogen activator \n(tPA) among patients in the National Institute of Neurological Disorders and \nStroke (NINDS) tPA stroke trials.\nMETHODS: We created the Stroke Prognostication using Age and NIH Stroke Scale \n(SPAN) index by combining age in years plus NIH Stroke Scale (NIHSS) ≥100. We \napplied the SPAN-100 index to patients in the NINDS tPA stroke trials (parts I \nand II) to evaluate its ability to predict clinical response and risk of \nintracerebral hemorrhage (ICH) after thrombolysis. The main outcome measures \nincluded ICH (any type) and a composite favorable outcome (defined as a modified \nRankin Scale score of 0 or 1, NIHSS ≤1, Barthel index ≥95, and Glasgow Outcome \nScale score of 1) at 3 months. Bivariate and multivariable logistic regression \nanalyses were used to determine the association between SPAN-100 and outcomes of \ninterest.\nRESULTS: Among 624 patients in the NINDS trials, 62 (9.9%) participants were \nSPAN-100 positive. Among those receiving tPA, ICH rates were higher for \nSPAN-100-positive patients (42% vs 12% in SPAN-100-negative patients; p < \n0.001); similarly, ICH rates were higher in SPAN-100-positive patients (19% vs \n5%; p = 0.005) among those not receiving tPA. SPAN-100 was associated with worse \noutcomes. The benefit of tPA, defined as favorable composite outcome at 3 \nmonths, was present in SPAN-100-negative patients (55.4% vs 40.2%; p < 0.001), \nbut not in SPAN-100-positive patients (5.6% tPA vs 3.9%; p = 0.76). Similar \ntrends were found for secondary outcomes (e.g., symptomatic ICH, catastrophic \noutcome, discharge home).\nCONCLUSION: The SPAN-100 index could be a simple method for estimating the \nclinical response and risk of hemorrhagic complications after tPA for acute \nischemic stroke. These results need further confirmation in larger contemporary \ndatasets.",
"1. ",
"BACKGROUND: Stroke Prognostication using Age and NIH (National Institutes of \nHealth) Stroke Scale (SPAN)-100 is a simple and easy-to-use tool for assessing \nthe outcomes of ischemic stroke after thrombolysis. To explore its application, \nwe evaluated SPAN-100's prognostic value in predicting 3- and 12-month outcomes \nin general ischemic stroke patients.\nMETHODS: We applied the SPAN-100 to ischemic stroke patients from the China \nNational Stroke Registry. Poor outcome was defined as a modified Rankin Scale of \n2-6. Discrimination of SPAN-100 was assessed by the area under the \nreceiver-operator curves (AUC) and 95% confidence intervals (CI). We also \nperformed an exploratory post hoc analysis of the performance of the SPAN index \nscore using 80 as the cutoff point.\nRESULTS: Among 11,894 ischemic stroke patients, 479 (4.0%) patients were \nSPAN-100 positive. The AUC of SPAN-100 for poor outcome was .54 (95% CI, \n.54-.54) at 3 months and .54 (95% CI, .54-.55) at 12 months, respectively. In \nthe exploratory analysis, when 80 was used as the cutoff point of SPAN index \nscore, the AUC for poor outcome was .66 (95% CI, .66-.67) at 3 months and .68 \n(95% CI, .67-.68) at 12 months, respectively.\nCONCLUSIONS: SPAN-100 suffered from low prediction power for 3- and 12-month \noutcomes of ischemic stroke in Chinese population. A cutoff point of 80 may \nimprove the performance, but none of them had an AUC above the threshold of .8 \nrequired for use in individuals.",
"BACKGROUND AND PURPOSE: Several prognostic scores have been developed to predict \nthe risk of symptomatic intracranial hemorrhage (sICH) after ischemic stroke \nthrombolysis. We compared the performance of these scores in a multicenter \ncohort.\nMETHODS: We merged prospectively collected data of patients with consecutive \nischemic stroke who received intravenous thrombolysis in 7 stroke centers. We \nidentified and evaluated 6 scores that can provide an estimate of the risk of \nsICH in hyperacute settings: MSS (Multicenter Stroke Survey); HAT (Hemorrhage \nAfter Thrombolysis); SEDAN (blood sugar, early infarct signs, [hyper]dense \ncerebral artery sign, age, NIH Stroke Scale); GRASPS (glucose at presentation, \nrace [Asian], age, sex [male], systolic blood pressure at presentation, and \nseverity of stroke at presentation [NIH Stroke Scale]); SITS (Safe \nImplementation of Thrombolysis in Stroke); and SPAN (stroke prognostication \nusing age and NIH Stroke Scale)-100 positive index. We included only patients \nwith available variables for all scores. We calculated the area under the \nreceiver operating characteristic curve (AUC-ROC) and also performed logistic \nregression and the Hosmer-Lemeshow test.\nRESULTS: The final cohort comprised 3012 eligible patients, of whom 221 (7.3%) \nhad sICH per National Institute of Neurological Disorders and Stroke, 141 (4.7%) \nper European Cooperative Acute Stroke Study II, and 86 (2.9%) per Safe \nImplementation of Thrombolysis in Stroke criteria. The performance of the scores \nassessed with AUC-ROC for predicting European Cooperative Acute Stroke Study II \nsICH was: MSS, 0.63 (95% confidence interval, 0.58-0.68); HAT, 0.65 (0.60-0.70); \nSEDAN, 0.70 (0.66-0.73); GRASPS, 0.67 (0.62-0.72); SITS, 0.64 (0.59-0.69); and \nSPAN-100 positive index, 0.56 (0.50-0.61). SEDAN had significantly higher \nAUC-ROC values compared with all other scores, except for GRASPS where the \ndifference was nonsignificant. SPAN-100 performed significantly worse compared \nwith other scores. The discriminative ranking of the scores was the same for the \nNational Institute of Neurological Disorders and Stroke, and Safe Implementation \nof Thrombolysis in Stroke definitions, with SEDAN performing best, GRASPS \nsecond, and SPAN-100 worst.\nCONCLUSIONS: SPAN-100 had the worst predictive power, and SEDAN constantly the \nhighest predictive power. However, none of the scores had better than moderate \nperformance.",
"IMPORTANCE: The Stroke Prognostication using Age and the NIH Stroke Scale index, \ncreated by combining age in years plus a National Institutes of Health (NIH) \nStroke Scale score of 100 or higher (and hereafter referred to as the SPAN-100 \nindex), is a simple risk score for estimating clinical outcomes for patients \nwith acute ischemic stroke (AIS). The association between this index and \nresponse to intravenous thrombolysis for AIS has not been properly evaluated.\nOBJECTIVE: To assess the relationship between SPAN-100 index status and outcome \nfollowing treatment with intravenous thrombolysis for AIS.\nDESIGN, SETTING, AND PARTICIPANTS: Using the Virtual International Stroke Trials \nArchive (VISTA) database, an international repository of clinical trials data, \nwe assessed the SPAN-100 index among 7093 patients with AIS who participated in \n4 clinical trials from 2000 to 2006. The SPAN-100 index is considered positive \nif the sum of the age and the NIH Stroke Scale (a 15-item neurological \nexamination scale with scores ranging from 0 to 42, with higher scores \nindicating more severe strokes) score is greater than or equal to 100. \nMultivariable logistic regression analyses were used to determine the \nindependent association between SPAN-100 index status and 90-day outcomes.\nMAIN OUTCOMES AND MEASURES: The primary outcome was a composite of severe \ndisability or death measured 90 days after stroke, and the secondary outcomes \nwere death alone and a composite of no disability/modest disability.\nRESULTS: Of 7093 patients, 743 (10.5%) were SPAN-100 positive, and 2731 (38.5%) \nreceived intravenous thrombolysis. Compared with SPAN-100-negative patients, \nSPAN-100-positive patients were more likely to experience a catastrophic outcome \n(adjusted odds ratio [AOR], 9.03 [95% CI, 6.68-12.21]) or death alone (AOR, 5.03 \n[95% CI, 4.06-6.23]) and less likely to experience a favorable outcome (AOR, \n0.08 [95% CI, 0.06-0.13]). However, there was an interaction between SPAN-100 \nindex status and thrombolysis treatment (P < .001) revealing a reduction in the \nlikelihood of severe disability/death with thrombolytic treatment for \nSPAN-100-positive (AOR, 0.46 [95% CI, 0.29-0.71]) but not SPAN-100-negative \npatients (AOR, 0.96 [95% CI, 0.85-1.07]). Similar interactions between SPAN-100 \nindex status and thrombolysis treatment were observed for the 2 secondary \noutcomes.\nCONCLUSION AND RELEVANCE: Compared with the SPAN-100-negative patients with AIS, \nthe SPAN-100-positive patients with AIS seem to have poorer 3-month outcomes but \nmay derive greater benefit when treated with intravenous thrombolysis. The \nSPAN-100-positive patients are often excluded from AIS clinical trials but \nshould probably not be denied thrombolysis treatment on the basis of such a \nprofile alone."
] | nan |
5a690487b750ff445500001f | [
24650116,
28761605,
1295944,
21886730,
24686796,
26275628,
22123662,
11369969,
21045362,
6270614,
28130396
] | train | Which virus can be diagnosed with the monospot test? | factoid | Epstein-Barr virus (EBV) can be detected with the monospot test. EBV is a highly prevalent virus, transmitted via saliva, which often causes asymptomatic infection in children but frequently results in infectious mononucleosis in adolescents. | Epstein-Barr virus | [
"BACKGROUND: Infection with Epstein-Barr virus (EBV) is almost ubiquitous in \nhumans and generally occurs at two ages: infantile, which is usually \nasymptomatic and associated with poorer socioeconomic conditions, and \nadolescent, which causes infectious mononucleosis (IM) in ~25% cases. The \ndeterminants of whether the infection causes IM remain uncertain. We aimed to \nevaluate seasonality and temporal trends in IM.\nMETHODS: Data from all Monospot tests, used as a marker for IM, were collected \nfrom the Grampian population over 16 years.\nRESULTS: Positive Monospot test results peaked at 17 years in females and 19 in \nmales. Females had 16% more diagnoses, although 55% more tests. IM was ~38% more \ncommon in winter than summer. The annual rate of positive tests decreased \nprogressively over the study period, from 174/100 000 (95% CI 171-178) in 1997 \nto 67/100 000 (95% CI 65-69) in 2012.\nCONCLUSIONS: IM appears to be decreasing in incidence, which may be caused by \nchanging environmental influences on immune systems. One such factor may be \nexposure to sunlight.Words 168.\nFUNDING: The Medical Research Council and NHS Grampian-MS endowments.",
"Henoch-Schönlein purpura (HSP) is the most common form of childhood vasculitis. \nVarious viral and bacterial infections, drugs, vaccines, food allergy and even \ninsect bites have been considered as triggering factors in pathogenesis of HSP. \nEpstein-Barr virus (EBV) infection, which is associated with HSP, have been \nrarely reported. Herein we present HSP patient possibly caused by EBV infection. \nA 8-year old boy was admitted to our department with fever, rashes on legs and \narms and intermittent mild abdominal pain. Multiple purpuric rashes were on his \nextremities, abdomen and buttock. Laboratory investigations revealed that \nmonospot test was positive, EBV serology tests; Anti-EA-D Ig G: 3+, Anti-VCA \ngp125 Ig G: 3+, Anti-VCA p19 Ig M: 2+, Anti EBNA-1 Ig M: negative, Anti EBNA-1 \nIg M: negative, Anti EBNA-1 Ig G: negative. The patient was interpreted as the \nprimary active acute EBV infection. A skin biopsy showed leucocytoclastic \nvasculitis. The other viral and bacterial investigations were negative. The \npatient was diagnosed as HSP vasculitis according to EULAR criteria and treated \nwith intravenous hydration and ibuprofen. He was discharged after 15 days with \nnormal laboratory findings and physical examination. We think that EBV infection \nmay be stimulant factor for autoimmune reactions and may cause HSP vasculitis. \nHence, it may be useful to investigate the EBV infection in etiology of HSP \ncases.",
"A study was carried out on 200 patients of ages 20-40 years suffering from acute \nviral hepatitis. Sera were tested for markers of hepatitis B (HBsAg, and IgM \nanti-HBc) and hepatitis A (IgM-anti-HAV) by the ELISA technique. Sera negative \nfor the markers of both viruses: Hepatitis A (HAV) and Hepatitis B (HBV) were \nsubsequently tested for IGM Heterophil antibodies against Epstein-Barr virus \n(EBV) by the Monospot slide test to diagnose acute infectious mononucleosis and \ntested for anti-CMV (IgM) by ELISA technique for the diagnosis of acute \nCytomegalovirus (CMV) infection. Non-A, non-B hepatitis (NANB) was diagnosed by \nexclusion. The results of the study showed that 133 (66.5%) patients had \nevidence of HBV infection, while only 9(4.5%) were diagnosed as HAV infection. \nEBV and CMV were the possible etiological agents of acute viral hepatitis in \n(3.5%) and 1%) respectively. Accordingly the Non-A, non-B hepatitis in this \nstudy amounts to (24.5%) of the acute viral hepatitis.",
"BACKGROUND: The rash in infectious mononucleosis is usually diffusely macular.\nMAIN OBSERVATIONS: A 15-year-old boy presented to us with high grade fever, sore \nthroat, malaise, body aches, and polyarthralgia. He developed annular, \nerythematous, and non-scaly eruptions on chest and right arm. Blanching erythema \nwas noted on his trunk. He had bilateral tender cervical lymph nodes, severe \npharyngeal congestion, petechiae on soft palate, uvular edema, infraorbital \nedema, and marginal tender hepatomegaly. Investigations revealed lymphocytosis \nand activated atypical lymphocytes in the peripheral smear, and positive \nmonospot test. The boy subsequently recovered in one week with total \ndisappearance of his rash. Epstein-Barr virus-related infectious mononucleosis \nwas considered the most likely diagnosis for our patient.\nCONCLUSIONS: To our knowledge, this atypical case is the third reported case of \nannular lesions in infectious mononucleosis. Dermatologists and other clinicians \nshould be alerted to this special presentation of primary EBV infection.",
"A 29-year-old man presented with sudden left-sided pleuritic chest pain on a \nbackground of sore throat during the preceding week. On examination he had \ntender cervical lymphadenopathy, he was tachycardic and had a 24 mm Hg blood \npressure difference between the left and right arms. Bloods revealed deranged \nliver function tests and a lymphocytosis. His D-dimer was raised, hence he was \ntreated for presumed pulmonary embolism before imaging was available. Monospot \ntest was positive. He subsequently had both a CT pulmonary angiogram and a CT \nangiogram of the aorta to exclude pulmonary embolism and aortic dissection. The \nCT revealed splenomegaly with a large subdiaphragmatic haematoma secondary to \nsplenic rupture. This had likely caused referred pain through diaphragmatic \nirritation. He was taken to theatre for urgent splenectomy. The unifying \ndiagnosis was infectious mononucleosis complicated by spontaneous splenic \nrupture secondary to Epstein-Barr virus infection.",
"A 75-year-old woman presented with altered mental status, septic picture, and \ninfluenza-like symptoms. Initial investigations revealed atypical lymphocytosis, \nthrombocytopenia, elevated liver enzymes, and a positive monospot test result. \nFurther investigation showed the Epstein-Barr virus viral capsid antibody \nIgM/IgG and Epstein-Barr virus DNA by polymerase chain reaction to be negative; \nhowever, interestingly her cytomegalovirus (CMV) IgM and IgG were positive, \nsuggesting that her mononucleosis-like syndrome was due to acute CMV infection. \nHerein, we report the first case of a heterophile-positive mononucleosis \nsyndrome caused by acute CMV infection in an elderly immunocompetent woman. This \ncase conveys that monospot test can yield false-positive result in the setting \nof acute CMV infection.",
"PURPOSE OF REVIEW: Infectious mononucleosis is a common, usually self-limited \ndisease. However, infectious mononucleosis may present with severe \nmanifestations. Complications may also occur. Consequently, diagnostic and \ntreatment issues regarding infectious mononucleosis are of major importance.\nRECENT FINDINGS: In this review, we focus on the evaluation of articles \nproviding diagnosis and treatment data for infectious mononucleosis, published \nduring the past 2 years. Twelve studies, deriving from extended search in \nPubMed, were included. Nine studies provided diagnosis data. The evaluated \ndiagnostic methods were real-time PCR (RT-PCR), IgM/IgG antibodies measured with \ndifferent assays [measurement of Epstein-Barr virus viral load (EBV-VL) in \nperipheral blood, neutrophil/lymphocyte/monocyte counts, C-reactive protein \nvalues, and monospot test]. The sensitivities reported for RT-PCR were high. The \navailable treatment data were scarce (three studies). Two of them suggested that \nantivirals (mainly acyclovir and valacyclovir) may have a role in the treatment \nof infectious mononucleosis with complications, whereas the remaining study \npresented novel potential therapeutic patents including 5-substituted uracyle, \nazacytosine derivatives, and peptides inhibiting EBV-mediated membrane fusion.\nSUMMARY: RT-PCR and measurement of EBV-VL may provide useful tools for the early \ndiagnosis of infectious mononucleosis in cases with inconclusive serological \nresults. Antiviral agents may provide a useful treatment option in patients with \nsevere infectious mononucleosis.",
"This case report is about an elderly man who presented with a long-standing \nhistory of high-grade fever and weight loss. He initially had only \nhepatosplenomegaly, but then developed jaundice. He also had pancytopenia and \nraised liver enzymes. His septic screen was negative, but he had a positive \nMonospot test and immunoglobulin G for Epstein-Barr virus. The liver biopsy \nshowed sinusoidal phagocytosis and the subsequent bone marrow aspiration and \nbiopsy showed significant hemophagocytosis, hence Hemophagocytic syndrome was \ndiagnosed. The fever was refractory to antibiotic and anti-tuberculosis therapy, \nbut it responded only partially to steroids. Full response was only noticed \nfollowing anti-viral treatment in the form of intravenous Ganciclovir. The \npatient's general condition, liver enzymes, bilirubin, hematological parameters \nand even the weight returned back to their normal range 2 weeks after \nGanciclovir therapy. Cessation of this drug resulted in relapse of his symptoms \nand oral antivirals did not help. Splenectomy, steroid pulse therapy and \nimmunosuppressive treatment were only partially helpful. Reintroduction of \nGanciclovir did help for a short period. We conclude that our patient had \nvirus-associated hemophagocytic syndrome most likely related to Epstein-Barr \nvirus infection, which was then confirmed by the splenic biopsy, and that \nGanciclovir can be of great help in eradicating the virus and treating the \ndisease, provided that it is given for a long enough period.",
"Infectious Mononucleosis (IM), a benign lymphoproliferative disease, is the best \nknown clinical syndrome caused by Epstein-Barr Virus (EBV). It usually resolves \nover a period of weeks or months without sequelae but may occasionally be \ncomplicated by a wide variety of neurologic, hematologic, hepatic, respiratory, \nand psychological complications. In this report we describe a patient with acute \nhepatitis following EBV-IM in a previously healthy woman. A 26-year-old woman \nwho presented with fever, generalized weakness, nausea, sore throat, yellowing \nof skin, and a generalized skin rash was admitted to our clinic. Tonsillar \nenlargement, pharyngeal erythema, palatal petechiae, lymphadenopathy, and \njaundice were noted. Significant atypical lymphocytes ( > 10%) were seen on the \nperipheral blood smear. Liver function tests such as ALT: 303 U/L, AST: 172 U/L, \nALP: 193 U/L and total bilirubin: 7.3 mg/dl were elevated. Serological tests for \nEBV infection were consistent with acute infection (EBV virus capsid antigen was \nreactive with IgM and IgG antibodies). The Monospot test was also positive. On \nthe seventh day, liver function tests and bilirubin had risen to peak level and \nplatelets were decreased. The patient was managed supportively and her critical \ncondition improved and was finally stabilized. Although the prognosis for IM is \nvery favorable, a variety of acute complications may occur.",
"Once acquired, Epstein-Barr virus (EBV), a latent virus, remains in the body for \nwhat appears to be the lifetime of the human host. Circumstantial data suggest \nEBV is involved in clinical disease including malignancies far more often than \npreviously recognized. A serologic test for early antigen (EA) is more specific \nfor diagnosing active EBV disease than the monospot or heterophile test. A case \nstudy of active Epstein-Barr infection is reported showing persistently elevated \nearly antigen titers prior to and following malignant transformation.",
"Epstein-Barr virus (EBV) is a highly prevalent virus, transmitted via saliva, \nwhich often causes asymptomatic infection in children but frequently results in \ninfectious mononucleosis in adolescents. Heterophile antibody tests, including \nthe Monospot test, are red cell or latex agglutination assays, which detect \nantired cell antibodies produced as part of a polyclonal antibody response \noccurring during EBV infection. Heterophile antibody tests are rapid, cheap and \nspecific tests that can be performed from the onset of symptoms of infectious \nmononucleosis. In adolescents, heterophile antibody tests have high specificity \nand sensitivity in the diagnosis of primary acute EBV infection. However, the \ntests have low sensitivity and low negative predictive value in young children \nand are not useful under the age of 4. Heterophile tests may be positive in \nother viral infections, autoimmune disease and haematological malignancies, but \ndo not appear to be positive in primary bacterial infection. Virus-specific \nserology is required in children under the age of 4 or if an older child is \nheterophile negative. Virus-specific serology allows diagnosis and the pattern \nof positivity and negativity enables the clinician to stage the EBV infection. \nVirus-specific serology appears to have better sensitivity in young children, \nbut there is cross-reaction with other herpesvirus infections, a longer \nturnaround time and it is more expensive to perform. Further research is needed \nto establish which children benefit from and hence require testing for \nheterophile antibodies, the cost-effectiveness of EBV investigations and whether \nheterophile titres have predictive value for the severity of infection and the \nlikelihood of complications."
] | ['http://amigo.geneontology.org/amigo/term/GO:0009597', 'https://meshb.nlm.nih.gov/record/ui?ui=D003933', 'https://meshb.nlm.nih.gov/record/ui?ui=D014780'] |
52bf1cad03868f1b0600000a | [
19725597,
11772283,
9814660,
11154213
] | train | Which virus is Cidofovir (Vistide) indicated for? | factoid | Cidofovir is commonly used in the treatment of cytomegalovirus (CMV) infection and disease. | cytomegalovirus | [
"Cytomegalovirus (CMV) infection is very common throughout the world, and has \nbecome more of a pediatric clinical concern given the high incidence of \ncongenital CMV infections as well as the increasing numbers of immunocompromised \npatients. Because of this, the need for antiviral therapies in infants and \nneonates is growing. Currently, there are four antivirals available that are \nactive against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. At \nthis time, none have approved indications for use in children. Although there \nare limited data regarding the dose, pharmacokinetics (PK), safety, and adverse \nevents for some of these antivirals, ganciclovir, and its oral prodrug \nvalganciclovir, have been the best studied in the infant and neonate \npopulations. In general, pharmaceutical PK studies in young children are limited \nby the constraints of sampling difficulties and blood volume requirements; fewer \nsampling times and studies may be available for drug evaluation. Given this \ncaveat, ganciclovir and valganciclovir PK in children thus far appears to follow \na monocompartmental model, contrary to what has been described in adults. \nHowever, when normalized for weight, the volume of distribution, clearance, and \nhalf-life of ganciclovir are similar to those found in adults. Given the \nfindings that ganciclovir (and thus valganciclovir) clearance is directly \nproportionate to renal function, care must be taken when administering the drug \nto patients with impaired renal function. Recent studies evaluating \nvalganciclovir PK in infants (at a dose of 16 mg/kg every 12 hours) have shown \nsimilar areas under the plasma concentration-time curve (AUCs) to intravenous \nganciclovir (at a dose of 6 mg/kg every 12 hours), and that these AUCs remain \nquite stable over a number of weeks. As seen in adults, oral ganciclovir has a \nlow bioavailability (4.8% in a pediatric analysis) and is therefore a poor \nalternative for treating serious CMV infections. Neutropenia is the most \nfrequent toxicity associated with ganciclovir and valganciclovir therapy, \nwhereas significant (and possibly irreversible) renal toxicity can be seen with \ncidofovir. Foscarnet administration can also result in renal toxicity as well as \nsignificant electrolyte imbalances. Several of these drugs have potential \ntoxicities that are of concern, including carcinogenesis, teratogenesis, and \nazospermia (ganciclovir, valganciclovir, and cidofovir) and deposition into bone \nor dentition (foscarnet) that may have significant implications when treating an \ninfant. Given these potential ill effects, careful consideration of the \nindications for the clinical use of these antivirals is necessary before using \nthem for CMV infection in neonates and infants.",
"Immunocompromised hosts are at increased risk of cytomegalovirus (CMV) infection \nand serious CMV disease. CMV infection is an important cause of morbidity among \npatients infected with HIV and after solid organ transplantation (SOT) and may \ncause life-threatening disease in allogeneic stem cell transplant (SCT) \nrecipients. The introduction into clinical use of potent antiviral compounds and \nof rapid detection assays for CMV during the past two decades has allowed \ndevelopment of strategies for the prevention and treatment of disease caused by \nCMV in these groups of immunocompromised patients. At present, the antiviral \ndrugs ganciclovir, foscarnet and cidofovir are commonly used in the treatment of \nCMV infection and disease. However, these agents have a poor oral \nbioavailability and, for systemic use, require iv. administration for most \nindications. Valganciclovir is an oral prodrug of ganciclovir, with a 10-fold \ngreater bioavailability than oral ganciclovir. Studies of the pharmacokinetics \nof valganciclovir among HIV-infected CMV-seropositive patients and liver \ntransplant recipients suggest that this oral compound has the potential to \nreplace both oral and iv. ganciclovir in many situations if it is shown to be as \nefficacious and safe as those ganciclovir formulations in immunodeficient \npatients. In the first part of this review, currently established approaches to \nthe management of CMV infection and disease in SCT and SOT recipients and \nHIV-infected patients are discussed to highlight possible indications for future \nvalganciclovir use; in the second part, data from human studies of \nvalganciclovir are presented.",
"Cytomegalovirus (CMV) infection remains a major cause of morbidity and mortality \nin recipients of an allogeneic stem cell transplant (SCT). Due to the broad \napplication of antiviral prophylaxis and preemptive therapy, a decrease in \nearly-onset and a subsequent increase in late-onset CMV disease has been \nobserved. New data on the latency state and reactivation of CMV have been \npresented, the role of T-cell responses in the control of CMV further \nsubstantiated, and viral immune escape mechanisms described in more detail. \nSensitive diagnostic assays using nucleic acid amplification and hybridization \ntechniques have been commercialized and will allow standardization of CMV \ndiagnostics in antiviral drug trials. Quantification of the viral load will be \nincreasingly considered for initiation and, in patients with persistence of high \nviral titers despite antiviral therapy, screening for antiviral drug resistance. \nClinical data are emerging to show that, apart from ganciclovir, foscarnet can \nbe given safely even after allogeneic SCT. Additional drugs like lobucavir and \ncidofovir have been used for specific indications. Interactions of \nimmunosuppressive drugs and antiviral compounds of clinical relevance have been \ndescribed. Thus, therapeutic drug monitoring and targeted antiviral drug dosing \nwill become standard practice in antiviral treatment strategies in patients \nfollowing allogeneic SCT.",
"A retrospective study was performed to collect information regarding efficacy \nand toxicity of cidofovir (CDV) in allogeneic stem cell transplant patients. \nData were available on 82 patients. The indications for therapy were \ncytomegalovirus (CMV) disease in 20 patients, primary preemptive therapy in 24 \npatients, and secondary preemptive therapy in 38 patients. Of the patients, 47 \nhad received previous antiviral therapy with ganciclovir, foscarnet, or both \ndrugs. The dosage of CDV was 1 to 5 mg/kg per week followed by maintenance every \nother week in some patients. The duration of therapy ranged from 1 to 134 days \n(median, 22 days). All patients received probenecid and prehydration. Ten of 20 \n(50%) patients who were treated for CMV disease (9 of 16 with pneumonia) \nresponded to CDV therapy, as did 25 of 38 (66%) patients who had failed or \nrelapsed after previous preemptive therapy and 15 of 24 (62%) patients in whom \nCDV was used as the primary preemptive therapy. Of the patients, 21 (25.6%) \ndeveloped renal toxicity that remained after cessation of therapy in 12 \npatients. Fifteen patients developed other toxicities that were potentially due \nto CDV or the concomitantly given probenecid. No toxicity was seen in 45 (61.6%) \npatients. Cidofovir can be considered as second-line therapy in patients with \nCMV disease failing previous antiviral therapy. However, additional studies are \nneeded before CDV can be recommended for preemptive therapy."
] | ['http://www.biosemantics.org/jochem#4236374', 'http://www.biosemantics.org/jochem#4261248'] |
58bfd0db02b8c60953000017 | [
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22688765,
10502526
] | train | Which virus type causes Molluscum contagiosum? | factoid | Molluscum contagiosum virus (MCV) is a human poxvirus that causes tumor-like skin lesions. | human poxvirus | [
"Molluscum contagiosum virus is a human and animal dermatotropic pathogen, which \ncauses a severe disease in immunocompromised individuals. MCV belongs to the \nPoxviridae family whose members exert immunomodulatory effects on the host \nantiviral response. Poxviruses interfere with cell signaling pathways that lead \nto the activation of nuclear factor кB, a pleiotropic transcription factor which \nis crucial for regulation of the immune response, the cell cycle and apoptosis. \nIn resting cells, NF-κB is present in the cytoplasm, where it is associated with \ninhibitor κB. Upon stimulation by activators, such as proinflammatory cytokines \nand bacterial or viral products, the inhibitory protein undergoes \nphosphorylation and proteasomal degradation. NF-κB, in turn, translocates to the \nnucleus, where it regulates the transcription of various genes that are \nessential for processes mentioned above. Since poxviruses replicate exclusively \nin the cell cytoplasm, NF-кB became a good target for poxviral immunomodulation. \nMCV encodes various proteins which interfere with the signaling pathways that \nlead to the activation of NF-κB. Ligand inhibitor encoded by MCV, MC54, binds \ninterleukin-18 and inhibits interferon-γ production. Other MCV proteins, MC159 \nand MC160, belong to intracellular inhibitors of NF-κB and are members of viral \nFLICE-inhibitory proteins (vFLIPs). MC159 protein encoded by MCV was shown to \ninhibit apoptosis of virus-infected cells. Such interactions serve immune \nevasion and are responsible for the persistence of MCV.",
"Molluscum contagiosum virus (MCV) is a poxvirus that causes localized papules in \nhealthy persons. We evaluated a woman with severe immunodeficiency and \ndisseminated MCV. During treatment with CMX-001, an antiviral with activity \nagainst other poxviruses, MCV DNA was detected in 20% of plasma samples. When \nthe patient was not receiving CMX-001, MCV DNA was detected in 50% of samples. \nWe also noted improvement in warts on her fingers during CMX-001 therapy. \nAlthough MCV is caused by direct inoculation of virus into skin in healthy \npersons, in a severely immunocompromised person MCV DNA was present in blood and \nmay spread by viremia.",
"Molluscum contagiosum (MC) is a very common benign self-limiting cutaneous viral \ninfection caused by molluscum contagiosum virus. Disease is self-limiting in \nimmunocompetent individuals, while it is severe and prolonged when associated \nwith Human Immunodeficiency Virus (HIV) infection. The widespread and refractory \nmollusca of HIV disease occur especially on the face. In advanced stages of \nimmunosuppression, giant or verrucous forms of MC may occur. Molluscum \ncontagiosum tends to take a chronic course and is usually not responsive to \nvarious treatments in immunocompromised patients. Here, we present a HIV \npositive male patient with extensive papulonodular lesions over face, neck, \nbilateral upper limbs since 2 months, diagnosed as giant molluscum contagiosum, \ntreated with cryotherapy with little improvement for few weeks after which \npatient did not turn up.",
"INTRODUCTION: Molluscum contagiosum is a common superficial skin infection \ncaused by the poxvirus, Molluscum Contagiosum virus. The study objective is to \nobtain a better understanding of physician practices and experiences with \nmolluscum contagiosum in order to focus informational and guidance material.\nMETHODS: A cross-sectional survey to assess medical practitioners' knowledge and \npractices with molluscum contagiosum was conducted using the 2009 DocStyles \nsurvey. Questions regarding category and number of molluscum contagiosum \npatients seen, treatments used and advice given to patients were included in the \nsurvey.\nRESULTS: Dermatologists saw the most cases, with the majority seeing 51-100 \nmolluscum contagiosum cases/year. The most common cases seen were children with \nmultiple lesions and adults with genital lesions. Respondents were most likely \nto recommend treatment to immunocompromised individuals, HIV patients, adults \nwith genital lesions and children with multiple lesions. Cryotherapy was the top \nchoice for all specialties with the exception of OB/GYNs, whose top choice was \ncurettage. \"Avoid intimate contact until lesions resolve\", \"Avoid touching \nlesions to reduce further spread\", and \"Don't be concerned, this will go away\" \nwere the top advice choices.\nDISCUSSION: Most survey respondents have dealt with molluscum contagiosum in \ntheir practice during the previous year. Overall, respondents picked appropriate \nchoices for treatment and advice given; however some ineffective or unnecessary \ntreatments were chosen and recommendations to prevent spread were chosen \ninfrequently. Knowledge gaps for appropriate transmission precaution advice \nmight cause unnecessary spread or autoinoculation. This survey has demonstrated \nthat molluscum contagiosum is a common infection seen by many types of \npractitioners and therefore guidance on treatment considerations and infection \ncontrol is valuable.",
"Molluscum contagiosum virus (MCV) is a poxvirus that causes tumor-like skin \nlesions. New evidence indicates that plasmacytoid dendritic cells, type I \ninterferon production, and interferon-induced dendritic cells have prominent \nroles in anti-MCV responses, and these features characterize the inflammatory \nresponse in lesions that will likely undergo spontaneous regression.",
"In recent years, our understanding of the role of natural killer (NK) cells in \nthe response to viral infection has grown rapidly. Not only do we realize \nviruses have many immune-evasion strategies to escape NK cell responses, but \nthat stimulation of NK cell subsets during an antiviral response occurs through \nreceptors seemingly geared directly at viral products and that NK cells can \nprovide a memory response to viral pathogens. Tremendous knowledge has been \ngained in this area through the study of herpes viruses, but appreciation for \nthe significance of NK cells in the response to other types of viral infections \nis growing. The function of NK cells in defense against poxviruses has emerged \nover several decades beginning with the early seminal studies showing the role \nof NK cells and the NK gene complex in susceptibility of mouse strains to \nectromelia, a poxvirus pathogen of mice. More recently, greater understanding \nhas emerged of the molecular details of the response. Given that human diseases \ncaused by poxviruses can be as lethal as smallpox or as benign as Molluscum \ncontagiosum, and that vaccinia virus, the prototypic member of the pox family, \npersists as a mainstay of vaccine design and has potential as an oncolytic virus \nfor tumor therapy, further research in this area remains important. This review \nfocuses on recent advances in understanding the role of NK cells in the immune \nresponse to poxviruses, the receptors involved in activation of NK cells during \npoxvirus infection, and the viral evasion strategies poxviruses employ to avoid \nthe NK response.",
"BACKGROUND AND AIMS: Molluscum contagiosum is caused by the molluscum \ncontagiosum virus (MCV) and is a very common skin disorder mainly involving \nyoung children Cryotherapy, curettage or some topical therapies have been \napplied for MC, but all of these treatments need several sessions, can be \nsomewhat ineffective, and very painful. The present study assessed the impact of \na single session of pulsed dye laser treatment of MC lesions which had proved \nresistant to other approaches Subjects and methods: Fifteen children comprised \nthe study subjects, 11 boys and 4 girls, 3-5 years of age (mean 4.2 yr) with \nrecalcitrant MC. Lesions were counted at baseline, and a single shot from a 585 \nnm pulsed dye laser was applied to each lesion (3 mm, 300 ms, 8.0 J/cm(2)). \nLesions were counted again at 1 week post-treatment and followed for up to 3 \nmonths thereafter.\nRESULTS: All patients completed the study and no patient dropped out through \npain or discomfort. Purpura was seen at each treated lesion immediately after \nirradiation, but at 1 week after treatment, lesion clearance was virtually \ncomplete which was maintained for 1 month, and no recurrence was seen at 3 \nmonths in 8 of the 15 patients who remained available for followup.\nCONCLUSIONS: A single treatment of MC lesions with the pulsed dye laser \nsuccessfully cured even recalcitrant lesions with no recurrence on follow up, \nand was well tolerated by the young subjects.",
"Basal and suprabasal layers of human epidermis infected with the poxvirus \nMolluscum contagiosum have been examined with the technique of serial \nsectioning. Phagocytic vacuoles, formerly not observed in human epidermis, were \nfound exclusively in the basal region. They did not fuse with other \nvirus-containing vacuoles or with lysosomes to form digestive vacuoles. Various \nstages of uncoating, preceding ejection of the virus core into the cytoplasm, \nwere observed in the virus-containing vacuole. Clusters of cores were commonly \nfound close to or even associated with centriolar structures. Their possible \ninterference with mitosis is discussed in relation to alterations observed in \nthe plasma membrane. It is assumed that excision of gap junction elements \nprecedes the induction of mitosis.",
"Molluscum contagiosum virus (MCV), the only member of the Molluscipoxvirus \ngenus, causes benign papules in healthy people but disfiguring lesions in \nimmunocompromised patients. The sequence of MCV has been completed, revealing \nthat MCV encodes a probable type I topoisomerase enzyme. All poxviruses \nsequenced to date also encode type I topoisomerases, and in the case of vaccinia \nvirus the topoisomerase has been shown to be essential for replication. Thus, \ninhibitors of the MCV topoisomerase might be useful as antiviral agents. We have \ncloned the gene for MCV topoisomerase, overexpressed and purified the protein, \nand begun to characterize its activities in vitro. Like other eukaryotic type I \ntopoisomerases, MCV topoisomerase can relax both positive and negative \nsupercoils. An analysis of the cleavage of plasmid and oligonucleotide \nsubstrates indicates that cleavage by MCV topoisomerase is favored just 3' of \nthe sequence 5' (T/C)CCTT 3', resulting in formation of a covalent bond to the \n3' T residue, as with other poxvirus topoisomerases. We identified solution \nconditions favorable for activity and measured the rate of formation and decay \nof the covalent intermediate. MCV topoisomerase is sensitive to inhibition by \ncoumermycin A1 (50% inhibitory concentration, 32 microM) but insensitive to five \nother previously reported topoisomerase inhibitors. This work provides the point \nof departure for studies of the mechanism of function of MCV topoisomerase and \nthe development of medically useful inhibitors.",
"Molluscum contagiosum is a viral infection of the skin and mucous membranes that \nis caused by infection with the molluscum contagiosum virus. Molluscum \ncontagiosum can be acquired from skin to skin contact which may be during play, \nin a swimming pool, or through sexual contact. Sexually acquired molluscum is \nrare in younger children, but becomes quite common during adolescence and young \nadulthood, after the sexual debut. It has been long known that the human \npapillomavirus, which causes genital warts, i.e., condyloma accuminatum, can be \nvertically transmitted through an infected genital tract. Children may not \nmanifest condyloma lesions for a few years. The entity of congenital molluscum \nhas been debated in the literature and only three cases of suspected congenital \nmolluscum have been reported. We report on four more infants with congenital \nmolluscum, two children with congenital lesions, and two children with onset of \nlesions at 6 weeks of age. Two children had single cutaneous lesions on the \nextremities and two had lesions of the scalp consistent with the site of \ncervical pressure. Congenital molluscum appears to be a more common entity than \npreviously reported. Vertical transmission of molluscum should be considered for \nall infantile cases of molluscum.",
"Some poxviruses and their mammalian hosts encode homologous proteins that bind \ninterleukin-18 (IL-18) with high affinity and inhibit IL-18-mediated immune \nresponses. MC54L, the IL-18 binding protein of the human poxvirus that causes \nmolluscum contagiosum, is unique in having a C-terminal tail of nearly 100 amino \nacids that is dispensable for IL-18 binding. When recombinant MC54L was \nexpressed and purified via a C-terminal six-histidine tag, a shorter fragment \nwas detected in addition to the full-length protein. This C-terminal fragment \nresulted from the cleavage of MC54L by cellular furin, as it was greatly \ndiminished when furin was specifically inhibited or when a furin-deficient cell \nline was used for expression. Furthermore, the N- and C-terminal fragments of \nMC54L were generated by cleavage of the recombinant protein with furin in vitro. \nThe furin cleavage site was mapped within a 32-amino-acid segment that is C \nterminal to the IL-18 binding domain. Full-length MC54L, but not the N-terminal \nIL-18 binding fragment, bound to cells and to purified heparin and other \nglycosaminoglycans that are commonly found on the cell surface and in the \nextracellular matrix. MC54L bound to heparin with a nanomolar K(d) and could \nsimultaneously bind to IL-18. Their different glycosaminoglycan and cell binding \nproperties may allow the long and short forms of MC54L to inactivate IL-18 near \nthe site of infection and at more distal locations, respectively.",
"Molluscum contagiosum poxvirus (MCV) type 1 and type 2 encode two chemokine-like \nproteins MC148R1 and MC148R2. It is believed that MC148R proteins function by \nblocking the inflammatory response. However, the mechanism of the proposed \nbiological activities of MC148R proteins and the role of the additional \nC-terminal cysteines that do not exist in other chemokines are not understood. \nHere, we demonstrated in two different assay systems that His-tagged MC148R1 \ndisplaces the interaction between CXCL12α and CXCR4. The N-terminal cysteines \nbut not the additional C-terminal cysteines modulate this displacement. \nHis-tagged MC148R1 blocked both CXCL12α-mediated and MIP-1α-mediated chemotaxis. \nIn contrast, MC148R2 blocked MIP-1α-mediated but not CXCL12α-mediated \nchemotaxis. Immunoprecipitation by antibodies to MC148R1 or CXCL12α followed by \nimmunoblotting and detection by antibodies to the other protein demonstrated \nphysical interaction of His-tagged CXCL12α and His-tagged MC148R1. Interaction \nwith chemokines might mask the receptor interaction site resulting in decreased \nbinding and impairment of the biological activities.",
"Infection with molluscum contagiosum virus, a poxvirus, normally has a typical \nclinical presentation; therefore, laboratory confirmation is infrequently sought \nand the virus is rarely isolated in culture. As reported herein, viral culture \nof specimens from atypical lesions may produce an abortive infection in limited \ncell lines and a cytopathic effect suggestive of herpes simplex virus.",
"Many viruses have evolved mechanisms for evading the host immune system by \nsynthesizing proteins that interfere with the normal immune response. The \npoxviruses are among the most accomplished at deceiving their hosts' immune \nsystems. The nucleotide sequence of the genome of the human cutaneous poxvirus, \nmolluscum contagiosum virus (MCV) type 1, was recently reported to contain a \nregion that resembles a human chemokine. We have cloned and expressed the \nchemokine-like genes from MCV type 1 and the closely related MCV type 2 to \ndetermine a potential role for these proteins in the viral life cycle. In \nmonocyte chemotaxis assays, the viral proteins have no chemotactic activity but \nboth viral proteins block the chemotactic response to the human chemokine, \nmacrophage inflammatory protein (MIP)-1alpha. Like MIP-1alpha, both viral \nproteins also inhibit the growth of human hematopoietic progenitor cells, but \nthe viral proteins are more potent in this activity than the human chemokine. \nThese viral chemokines antagonize the chemotactic activity of human chemokines \nand have an inhibitory effect on human hematopoietic progenitor cells. We \nhypothesize that the inhibition of chemotaxis is an immune evasion function of \nthese proteins during molluscum contagiosum virus infection. The significance of \nhematopoietic progenitor cell inhibition in viral pathogenesis is uncertain.",
"Molluscum contagiosum is a common skin and mucosal disease of viral origin, \ncaused by molluscum contagiosum virus (MCV) virus of poxvirus family. With the \neradication of smallpox, MCV is now the only member of the poxvirus family that \ncauses substantial disease in humans. Though frequently reported, its unusual \nclinical presentation makes its diagnosis a challenging task. We discuss a case \nof molluscum contagiosum in a 30-year-old woman along with a review of \naetiology, histopathology and different possible treatment modalities.",
"Molluscum contagiosum is a benign contagious disease caused by a poxvirus. The \nvirus proliferates within keratinocytes and forms intracytoplasmic Molluscum \nbodies. Though it is a common clinical condition, histologically is not yet \nreported from this region of Mymensingh. We received a skin biopsy specimen in a \npathology laboratory for histological examination. The Haematoxylin and Eosin \nstained sections revealed typical intracytoplasmic Molluscum bodies in \nkeratinocytes. The lesions were in the trunk, which is a common site for \nMolluscum Contagiosum (MC). As the diagnosis of Molluscum contagiosum is easy by \nhistological examination, every patient suspected to be this disease is \nrecommended to be examined histologically to exclude other similar types of \nlesions.",
"Molluscum contagiosum is a virus that causes characteristic pearly lesions on \nthe surface of the skin. Small clusters of mollusca are a nuisance rather than a \nserious health problem. However, the mollusca can be more widespread and \ndisfiguring in people with impaired cell-mediated immunity. Molluscum \ncontagiosum virus is common in children. In adults it can also be contracted \nduring sexual activity and might indicate a need for diagnostic testing for \nother, more serious sexually transmitted infections in young, sexually active \nadults.",
"Molluscum contagiosum virus (MCV) is a member of the family Poxviridae and \npathogenic to humans. MCV causes benign epidermal tumors mainly in children and \nyoung adults and is a common pathogen in immunecompromised individuals. The \nviral DNA polymerase is the essential enzyme involved in the replication of the \ngenome of DNA viruses. The identification and characterization of the gene \nencoding the DNA polymerase of molluscum contagiosum virus type 1 (MCV-1) was \ncarried out by PCR technology and nucleotide sequence analysis. Computer-aided \nanalysis of known amino acid sequences of DNA polymerases from two members of \nthe poxvirus family revealed a high amino acid sequence homology of about 49.7% \nas detected between the DNA polymerases of vaccinia virus (genus Orthopoxvirus) \nand fowlpoxvirus (genus Avipoxvirus). Specific oligonucleotide primers were \ndesigned and synthesized according to the distinct conserved regions of amino \nacid sequences of the DNA polymerases in which the codon usage of the MCV-1 \ngenome was considered. Using this technology a 228 bp DNA fragment was amplified \nand used as hybridization probe for identifying the corresponding gene of the \nMCV-1 genome. It was found that the PCR product was able to hybridize to the \nBamHI MCV-1 DNA fragment G (9.2 kbp, 0.284 to 0.332 map units). The nucleotide \nsequence of this particular region of the MCV-1 genome (7267 bp) between map \ncoordinates 0.284 and 0.315 was determined. The analysis of the DNA sequences \nrevealed the presence of 22 open reading frames (ORFs-1 to -22). ORF-13 (3012 \nbp; nucleotide positions 6624 to 3612) codes for a putative protein of a \npredicted size of 115 kDa (1004 aa) which shows 40.1% identity and 35% \nsimilarity to the amino acid sequences of the DNA polymerases of vaccinia, \nvariola, and fowlpoxvirus. In addition significant homologies (30% to 55%) were \nfound between the amino acid sequences of the ORFs 3, -5, -9, and -14 and the \namino acid sequences of the E6R, E8R, E10R, and a 7.3 kDa protein of vaccinia \nand variola virus, respectively. Comparative analysis of the genomic positions \nof the loci of the detected viral genes including the DNA polymerases of MCV-1, \nvaccinia, and variola virus revealed a similar gene organization and \narrangement.",
"BACKGROUND: Molluscum contagiosum (MC) is caused by a DNA virus of the poxvirus \ngroup. It is common in children, and is also found in sexually active adults and \nHIV-seropositive patients. Cellular immunity is essential to controlling MC \nvirus infection. We report the first observation of a patient with stage IV \nSezary syndrome, who presented multiple molluscum contagiosum, spread and \nsurrounded by a pale halo.\nCASE REPORT: A woman aged 70 presented with aggravation of Sezary syndrome \ndiagnosed in 2009 and treated with topical corticosteroids. The examination \nshowed a generalized pruritic exanthem and multiple flesh-coloured papules from \n1 to 3 mm, spread over the entire skin surface and surrounded by a white halo. \nHistological examination of a lesion showed the presence of infected cells with \nintracytoplasmic inclusions infected in an acanthotic epidermis, surrounded by a \nmelaninopenic hypomelanosis with a normal melanocyte density. There was no \ninflammatory character. The diagnosis of multiple molluscum contagiosum was \ngiven, the application of clobetasol propionate was suspended and treatment with \nchlorambucil 4 mg/day and prednisone 0.5 mg/kg/day was started. The evolution of \nthe rash and pruritus was rapidly favourable. After 3 months, the rash and \npruritus had regressed. There was no molluscum contagiosum or clear halo.\nCONCLUSION: We report the original observation of a patient with stage IV Sezary \nsyndrome, who presented multiple molluscum contagiosum, spread and surrounded by \na pale halo, without inflammation, eczema or disappearance of melanocytes. This \nhalo could be due to the secretion of a protein by molluscum contagiosum \ninhibiting inflammation around this MC. To our knowledge, this phenomenon \nreported in a patient with severe atopic dermatitis associated with Sezary \nsyndrome has not previously been described.",
"Molluscum contagiosum virus (MCV) causes persistent neoplasms in healthy and \nimmunocompromised people. Its ability to persist likely is due to its arsenal of \nviral immunoevasion proteins. For example, the MCV MC159 protein inhibits \nTNF-R1-induced NF-κB activation and apoptosis. The MC159 protein is a viral FLIP \nand, as such, possesses two tandem death effector domains (DEDs). We show in \nthis article that, in human embryonic kidney 293 T cells, the expression of \nwild-type MC159 or a mutant MC159 protein containing the first DED (MC159 A) \ninhibited TNF-induced NF-κB, or NF-κB activated by PMA or MyD88 overexpression, \nwhereas a mutant protein lacking the first DED (MC159 B) did not. We \nhypothesized that the MC159 protein targeted the IκB kinase (IKK) complex to \ninhibit these diverse signaling events. Indeed, the MC159 protein, but not MC159 \nB, coimmunoprecipitated with IKKγ. MC159 coimmunoprecipitated with IKKγ when \nusing mouse embryonic fibroblasts that lack either IKKα or IKKβ, suggesting that \nthe MC159 protein interacted directly with IKKγ. MC159-IKKγ \ncoimmunoprecipitations were detected during infection of cells with either MCV \nisolated from human lesions or with a recombinant MC159-expressing vaccinia \nvirus. MC159 also interacts with TRAF2, a signaling molecule involved in NF-κB \nactivation. However, mutational analysis of MC159 failed to reveal a correlation \nbetween MC159-TRAF2 interactions and MC159's inhibitory function. We propose \nthat MC159-IKK interactions, but not MC159-TRAF2 interactions, are responsible \nfor inhibiting NF-κB activation.",
"We report here the clinical and immunological findings in two patients with \nmolluscum contagiosum poxvirus infection and the acquired immunodeficiency \nsyndrome (AIDS). These cases support earlier evidence that the molluscum \ncontagiosum virus may act as cases support earlier evidence that the molluscum \ncontagiosum virus may act as an opportunistic pathogen. There is now evidence \nthat members of all five families of double stranded DNA-containing human \nviruses have been associated with unusual clinical manifestations in AIDS \npatients, and the significance of DNA virus infections in patients with AIDS is \ndiscussed.",
"BACKGROUND: Molluscum contagiosum virus (MCV) causes molluscum contagiosum (MC) \nin both children and adults. Recent studies have revealed that the DNA of MCV \ncan be classified into two major types by restriction enzyme cleavage patterns; \nhowever, the relationship between MCV types and the clinical features has not \nbeen fully understood. Our study was conducted to examine whether there are \ngeographic differences in the incidence of MCV types and whether a correlation \nexists between MCV types and the age, sex, and clinical status of the patients.\nMETHODS: Specimens were obtained from 171 Japanese patients. The total DNA was \nextracted and digested with the restriction enzymes, BamH I, Hind III, and Cla \nI, respectively. Specimens were then electrophoresed in agarose gels. The gels \nwere stained with ethidium bromide and photographs were taken under \ntransillumination.\nRESULTS: Six different cleavage patterns were observed; they were classified \ninto two major types, MCV 1 and MCV 2, consisting of two MCV 1-variants, and MCV \n2 prototype, and three MCV 2-variants. The ratio of MCV 1 to MCV 2 was 13:1. MCV \n1 was commonly detected in children (98%) and adult women (92%). MCV 2 was more \nfrequently isolated from adult men (44%) and from patients with human \nimmunodeficiency virus (HIV) infection (75%).\nCONCLUSION: MCV types found in Japanese children and adult women were \npredominantly MCV 1 and less frequently MCV 2. This pattern is similar to that \nobserved in European countries and Australia, suggesting a high frequency and \nworld-wide distribution of MCV 1. The higher incidence of MCV 2 among adult men \nand HIV-positive patients may indicate that transmission routes of MCV 1 and MCV \n2 is somewhat different, of which the latter may be in part by sexual contact.",
"Molluscum contagiosum virus (MCV) is a common, human poxvirus that causes small \npapular skin lesions that persist for long periods without signs of \ninflammation. Previous studies revealed that MCV encodes a family of proteins \nwith homology to mammalian IL-18 binding proteins. IL-18 is a proinflammatory \ncytokine that induces synthesis of interferon gamma, activates NK cells, and is \nrequired for a T-lymphocyte helper type 1 response. We expressed and purified \nthe proteins encoded by the MC53L and MC54L genes of MCV, as well as their human \nand murine homologs. All four recombinant proteins were able to bind with high \naffinity to human and murine IL-18 molecules and inhibited IL-18 mediated \ninterferon gamma production in a dose-dependent manner. The pirating of IL-18 \nbinding proteins by poxviruses and their use as decoy receptors is consistent \nwith the critical role of IL-18 in defense against virus infections and provides \na mechanism for evasion of the immune system by MCV.",
"BACKGROUND: Molluscum contagiosum virus (MCV) causes an innocuous yet persistent \nskin infection in immunocompetent individuals and is spread by contact with \nlesions. Studies point to atopic dermatitis (AD) as a risk factor for MCV \ninfection; however, there are no longitudinal studies that have evaluated this \nhypothesis.\nMETHODS: Outpatient visit data from fiscal years 2001-2009 for American Indian \nand Alaska Native (AI/AN) children were examined to describe the incidence of \nmolluscum contagiosum (MC). We conducted a case-control study of patients <5 \nyears old at an Indian Health Service (IHS) clinic to evaluate dermatological \nrisk factors for infection.\nRESULTS: The incidence rate for MC in children <5 years old was highest in the \nWest and East regions. MC cases were more likely to have a prior or co-occurring \ndiagnosis of eczema, eczema or dermatitis, impetigo, and scabies (p<0.05) \ncompared to controls; 51.4% of MC cases had a prior or co-occurring diagnosis of \neczema or dermatitis.\nCONCLUSIONS: The present study is the first demonstration of an association \nbetween AD and MC using a case-control study design. It is unknown if the \nconcurrent high incidence of eczema and MC is related, and this association \ndeserves further investigation.",
"Molluscum contagiosum virus (MCV), a poxvirus pathogenic for humans, replicates \nwell in human skin in vivo, but not in vitro in standard monolayer cell \ncultures. In order to determine the nature of the replication deficiency in \nvitro, the MCV infection process in standard culture has to be studied step by \nstep. The method described in this chapter uses luciferase and GFP reporter \nconstructs to measure poxviral mRNA transcription activity in cells in standard \nculture infected with known quantities of MCV or vaccinia virus. Briefly, MCV \nisolated from human tissue specimen is quantitated by PCR and used to infect \nhuman HEK293 cells, selected for ease of transfection. The cells are \nsubsequently transfected with a reporter plasmid encoding firefly luciferase \ngene under the control of a synthetic early/late poxviral promoter and a control \nplasmid encoding a renilla luciferase reporter under the control of a eukaryotic \npromoter. After 16 h, cells are harvested and tested for expression of \nluciferase. MCV genome units are quantitated by PCR targeting a genome area \nconserved between MCV and vaccinia virus. Using a GFP reporter plasmid, this \nmethod can be further used to infect a series of epithelial and fibroblast-type \ncell lines of human and animal origin to microscopically visualize MCV-infected \ncells, to assess late promoter activation, and, using these parameters, to \noptimize MCV infectivity and gene expression in more complex eukaryotic cell \nculture models.",
"All poxviruses studied encode a type 1B topoisomerase that introduces transient \nnicks into DNA and thereby relaxes DNA supercoils. Here we present a study of \nthe protein domains of the topoisomerase of the poxvirus molluscum contagiosum \n(MCV), which allows us to specify DNA contacts made by different domains. \nPartial proteolysis of the enzyme revealed two stable domains separated by a \nprotease-sensitive linker. A fragment encoding the linker and carboxyl-terminal \ndomain (residues 82-323) was overexpressed in Escherichia coli and purified. MCV \ntopoisomerase (MCV-TOP)(82-323) could relax supercoiled plasmids in vitro, \nalbeit with a slower rate than the wild-type enzyme. MCV-TOP(82-323) was \nsensitive to sequences in the favored 5'-(T/C)CCTT-3' recognition site and also \nflanking DNA, indicating that some of the sequence-specific contacts are made by \nresidues 82-323. Assays of initial binding and covalent catalysis by \nMCV-TOP(82-323) identified the contacts flanking the 5'-CCCTT-3' sequence at \n+10, +9, -2, and -3 to be important. Tests with substrates containing a \n5-bridging phosphorothiolate that trap the cleaved complex revealed that correct \ncontacts to the flanking sequences were important in the initial cleavage step. \nMCV-TOP(82-323) differed from the full-length protein in showing reduced \nsensitivity to mutations at a position within the 5'-(T/C)CCTT-3' recognition \nsite, consistent with a model in which the amino-terminal domain contacts this \nregion. These findings provide insight into the division of labor within the \nMCV-TOP enzyme."
] | ['http://www.disease-ontology.org/api/metadata/DOID:8867', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008977', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008976'] |
517a8c918ed59a060a000043 | [
18039618,
8199011,
18277927,
3889351,
2641165,
14993139
] | train | Which viruses are best known to cause myocarditis? | list | The most frequent viruses causing myocarditis are Enterovirus, Adenovirus and Coxsackie B viruses. | ['Enterovirus', 'Adenovirus', 'Coxsackie B virus'] | [
"Enteroviruses have been considered to be the most common cause of acute \nmyocarditis and possible consequence of dilated cardiomyopathy. Some \npublications shed light to the role of other viruses in this disease as well. \nOur molecular investigation has demonstrated that adeno- and herpes viruses \nmight also frequently occur in dilated cardiomyopathy.\nAIM: The aim of our study was to screen virus genomes in heart tissues from \nheart-transplanted patients to prove their possible role in the pathogenesis of \ndilated cardiomyopathy.\nMETHODS: DNA and RNA were isolated from five regions of the heart muscle. \nAmplification for Adenovirus Type 3, Human Herpes Virus Type 6 and Enterovirus \ngenomes were performed by nested-Polymerase Chain Reaction. Finally the \nvirus-positive samples were direct sequenced.\nRESULTS: In 2 patients Adenovirus Type 3 and in 1 patient both Adenovirus Type 3 \nand Human Herpes Virus Type 6 were detected. No enteroviruses were found in any \nheart tissue.\nCONCLUSIONS: In our study the adenovirus genome was found to be the most \nfrequent virus genome in explanted heart tissues. The identified viral sequences \nproved previous viral infection, which could have played a role in the \ndevelopment of dilated cardiomyopathy. Detection of different viruses in the \nmyocardium by molecular biological examinations might contribute to adequate \ntreatment of these patients.",
"A transfection-reactivated Coxsackievirus B3 (rCVB3), from a full-length cDNA \nclone of Nancy strain, has previously been shown to be as cardiovirulent as the \nwild-type virus. Myocarditis induced by this genetically defined virus was \ncompared in SWR mice with the traditional Balb/c model. SWR mice inoculated with \nrCVB3 developed more severe myocarditis but less severe pancreatitis than Balb/c \nmice. In contrast to the poor general health and frequent mortality of Balb/c \nmice following CVB3 infection, the body weight of SWR mice was not affected by \nCVB3 inoculation and no mortality occurred at titres of 10(2)-10(7) plaque \nforming units (PFU). Typical myocarditis developed in SWR mice 7 days post \ninfection. Myocarditic foci consisting of necrotic myocardial fibres and \nmononuclear cell infiltrates resolved by day 30, similar to that observed in \nBalb/c. However, SWR mice were more sensitive to rCVB3-induced myocarditis than \nwere Balb/c mice: mild myocarditis was induced (4/4) by as low as 10(2) PFU of \nthe virus (ID50 < 10(1.5) PFU), and more severe myocarditis was seen at higher \nPFU of virus in a dose-dependent manner. The SWR model was tested with \nattenuated variants derived from cardiovirulent rCVB3. The ID50 for myocarditis \nwas 10(7) PFU for a large plaque-size attenuant and 10(6) PFU for a minute \nplaque-size attenuant, indicating loss of cardiovirulence by a factor of more \nthan 10(4)-10(5). rCVB3-induced SWR mouse is a sensitive and reliable model for \nmyocarditis. It is useful in assessing the cardiovirulence of different CVB3 \nvariants and evaluating the efficacies of anti-viral therapies. It will allow \nfollow-up study after high dose infection with cardiovirulent rCVB3.",
"BACKGROUND: Enteroviruses (EV) are an important cause of neonatal disease \nincluding hepatitis, meningoencephalitis, and myocarditis that can lead to death \nor severe long-term sequelae. Less is known about severe neonatal infection \ncaused by the parechoviruses (PeV) of which type 1 (PeV1) and type 2 (PeV2) were \npreviously known as echovirus 22 and echovirus 23. They belong to the same \nfamily of Picornaviridae as the EV. Of the PeV, so far only PeV3 has been \nassociated in 2 recent reports with severe neonatal infection including \ninvolvement of central nervous system.\nMETHODS: We compared the clinical signs, diagnosis, laboratory data, cerebral \nimaging, and neurodevelopmental outcome of 11 neonates with PeV infection with \n21 infants with EV infection treated in our hospital between 1994 and 2006. The \ndiagnosis of EV infection or PeV infection was confirmed by a positive EV and/or \nPeV real time-polymerase chain reaction on blood, cerebrospinal fluid, (CSF) or \nstool or a viral culture of stool, nasopharyngeal swab, and/or CSF.\nRESULTS: The 32 infants presented with sepsis-like illness and the most frequent \nsigns were: fever, seizures, irritability, rash, and feeding problems. All \npatients received antibiotic treatment. Eleven of 21 infants infected with EV \nand 7 of 11 infants infected with PeV were full-term. Differentiation between \nthe infants infected with EV and PeV on the basis of fever, irritability, rash, \nand seizures was not possible. Myocarditis was exclusively seen in 4 patients \ninfected by EV. Eight of 11 patients with a PeV infection had \nmeningoencephalitis of whom only 1 infant developed pleocytosis in the CSF. \nSerum C-reactive protein and CSF protein values were significantly higher in \ninfants with EV infection than in those with PeV infection. Cerebral imaging of \nall infants with EV or PeV cerebral infection showed mild to severe white matter \nabnormalities. In 1 infant with EV infection and 3 infants with PeV infection, \nneurodevelopmental delay occurred. Mortality and long-term sequelae were mainly \nassociated with myocarditis in the infants who were infected with EV (4 of 21).\nCONCLUSIONS: It is not possible to distinguish neonatal PeV from EV infection on \nthe basis of clinical signs. Neonates with PeV or EV infection present with \nsepsis-like illness and the most frequent signs are fever, seizures, \nirritability, rash, and feeding problems.",
"Coxsackie B viruses (types 1 to 5) are the most frequent reported cause of acute \nviral myocarditis. To study the pathogenesis of the disease at the cellular \nlevel, we simulated an infectious situation by infecting cultured human foetal \nheart cells with Coxsackie B3 (CB3) virus. Successful replication of this virus \ncould be demonstrated by the presence of virus particles inside cultivated \nfoetal myocytes together with high titres of progeny virus of 10(8) \nplaque-forming units (PFU) per millilitre culture medium. Within 9 h of \ninfection networks of myocytes lost their ability to contract spontaneously \nfollowed by disintegration and replacement by overgrowing fibroblasts which \nsurvived the infection. These cells produced CB3 virus continuously over several \nmonths, indicating carrier state infection of human myocardial fibroblasts. \nHuman fibroblasts interferon (IFN-beta) was found to act as a potent inhibitor \nof the replication of this virus. Virus yields could be reduced from 1.2 x 1.8 x \n10(5) PFU/ml culture medium when human heart cells were incubated with IFN-beta \n20 h prior to challenge with a high input multiplicity of 50 PFU of CB3 virus \nper cell, demonstrating the major protective role of IFN-beta in CB3 viral \ninfection. It thus appear that IFN-beta might become useful as an antiviral \nagent in the treatment of Coxsackie myocarditis.",
"The results are presented of serological tests by the neutralization method for \nantigens of Coxsackie B group, and by the haemagglutination inhibition method \nfor three types of parainfluenza and sporadic influenza virus in 529 patients \nwith myocarditis. In 7 cases the virus was isolated from stools. Virus aetiology \nof the disease was confirmed in 23.4% of cases, on average. Raised levels of \nantibodies to Coxsackie B antigens were found more frequently than the levels of \nantibodies to parainfluenza viruses. Seroconversion was more frequent in \ninfections by parainfluenza type 3 than type 2. During an influenza epidemic in \n5 cases raised levels of antibodies to the epidemic-causing strain were \nobserved.",
"BACKGROUND: Myocarditis can occasionally lead to sudden death and may progress \nto dilated cardiomyopathy in up to 10% of patients. Because the initial onset is \ndifficult to recognize clinically and the diagnostic tools available are \nunsatisfactory, new strategies to diagnose myocarditis are needed.\nMETHODS AND RESULTS: Cardiovascular MR imaging (CMR) was performed in 32 \npatients who were diagnosed with myocarditis by clinical criteria. To determine \nwhether CMR visualizes areas of active myocarditis, endomyocardial biopsy was \ntaken from the region of contrast enhancement and submitted to histopathologic \nanalysis. Follow-up was performed 3 month later. Contrast enhancement was \npresent in 28 patients (88%) and was usually seen with one or several foci in \nthe myocardium. Foci were most frequently located in the lateral free wall. In \nthe 21 patients in whom biopsy was obtained from the region of contrast \nenhancement, histopathologic analysis revealed active myocarditis in 19 patients \n(parvovirus B19, n=12; human herpes virus type 6 [HHV 6], n=5). Conversely, in \nthe remaining 11 patients, in whom biopsy could not be taken from the region of \ncontrast enhancement, active myocarditis was found in one case only (HHV6). At \nfollow-up, the area of contrast enhancement decreased from 9+/-11% to 3+/-4% of \nleft ventricular mass as the left ventricular ejection fraction improved from \n47+/-19% to 60+/-10%.\nCONCLUSIONS: Contrast enhancement is a frequent finding in the clinical setting \nof suspected myocarditis and is associated with active inflammation defined by \nhistopathology. Myocarditis occurs predominantly in the lateral free wall. \nContrast CMR is a valuable tool for the evaluation and monitoring of \ninflammatory heart disease."
] | nan |
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] | train | Which vitamin deficiencies may present with neurologic signs or symptoms? | list | Many vitamin deficiencies have been described as a cause of neurologic signs and symptoms. For instance, vitamin B12 deficiency can cause several types of neurological manifestations, such as subacute combined degeneration of the spinal cord, ataxia, peripheral polyneuropathy, optic nerve neuropathy, and cognitive disorders. In addition, vitamin B1 (Thiamine) and B6 (Pyridoxine) deficiency can both cause peripheral neuropathy. Specifically, vitamin B1 deficiency can also cause confusion, ophthalmoplegia, nystagmus, and ataxia in the context of beriberi and Wernicke's encephalopathy. Finally, vitamin A deficiency has been described to cause retinal change-related visual defects and subsequent vision loss. | ['Vitamin B12', 'Vitamin A', 'Vitamin B1', 'Vitamin B6', 'Vitamin E', 'Vitamin D'] | [
"We describe nine patients with fat malabsorption in whom a spectrum of vitamin E \ndeficiency was present. Early deficiency was generally asymptomatic, and \nintermediate deficiency produced some impairment. Ataxia, weakness, reflex \nchanges, impaired vision, and pigment retinopathy were associated with chronic, \nadvanced deficiency. In the last group, delayed central somatosensory conduction \nand amplitude reduction of the electroretinogram were present. In adults, a \nsevere vitamin E deficiency state existed for more than 5 years before producing \nmeasurable neurologic damage. The clinical picture is less homogeneous than \npreviously suggested, and electrophysiologic abnormalities need not predate \nclinical dysfunction.",
"Cobalamin deficiency is associated with a wide spectrum of hematologic, \nneurologic, gastroenterologic and psychiatric disorders or symptoms. We report a \ncase of a 50-year-old man with complex partial seizures with secondary \ngeneralization, mood oscillations and psychotic symptoms alternating with \nconfusion and reversible dementia secondary to cobalamin deficiency in the \nabsence of typical neurologic and/or hematologic symptoms and signs. Exclusion \nof epilepsy, acute, atrophic or expansive lesion of central nervous system and \nusual etiology associated with reversible dementia (infectious diseases, an \nendocrine etiology and deficiency of vitamins other than cobalamin); finding of \ncobalamin deficiency only and complete neuropsychiatric recovery after \nsubstitution, confirmed etiology. Typical and atypical psychiatric \nmanifestations due to cobalamin deficiency that precede neurologic and/or \nhematologic signs and symptoms can recover completely after adequate replacement \ntherapy.",
"We report herein our interesting case series of 15 infants admitting with \nneurological symptoms who were found to have vitamin B12 deficiency. Infants who \nwere admitted to our hospital between 2004 and 2007 with neurological symptoms \nand were found to have vitamin B12 deficiency were included in this study. Data \nregarding clinical and laboratory features were obtained. Of 15 infants, 9 were \nboys (60%) and 6 were girls (40%). The mean age was 11.7 months. Anorexia, \npallor, hypotonia, and neurodevelopmental retardation were present in all \ninfants. Seizures and tremor were observed in 46.6% (7/15) and 33% (5/15) of \npatients, respectively. Seizures were generalized tonic-clonic in 4 patients, \ngeneralized tonic in 1 patient and focal in 2 patients. Four patients had tremor \non admission and 1 patient had occurrence after vitamin B12 treatment. Vitamin \nB12 deficiency may lead to serious neurological deficits in addition to \nmegaloblastic anemia. Persistent neurological damage can be prevented with early \ndiagnosis and treatment. We believe that a thorough clinical and neurological \nassessment might prevent failure to notice rare but possible vitamin B12 \ndeficiency in infants with neurological deficits and neurodevelopmental \nretardation.",
"Thirteen children, aged 10 months to 20 years, presenting with chronic \ncholestasis from the first month of life and with low serum levels of vitamins A \nand/or E, have been investigated for neurological and ophthalmological symptoms. \nClinical findings consisted of 4 types: peripheral neuropathy; cerebellar \ndysfunction; abnormalities of eye movement, and retinal degenerative changes. \nThe results of electrophysiological and morphological studies of muscle and \nnerves were consistent with neurono-axonal degeneration. Electrical \nabnormalities of the retina, especially a decrease of the b wave of \nelectroretinogram, appear to be the first sign of the syndrome, allowing early \ndetection. Evidence for vitamin deficiency (E or E+A) suggests substitutive \nparenteral treatment in such patients.",
"We reviewed 153 episodes of cobalamin deficiency involving the nervous system \nthat occurred in 143 patients seen over a recent 17-year period at 2 New York \nCity hospitals. Pernicious anemia was the most common underlying cause of the \ndeficiency. Neurologic complaints, most commonly paresthesias or ataxia, were \nthe first symptoms of Cbl deficiency in most episodes. The median duration of \nsymptoms before diagnosis and treatment with vitamin B12 was 4 months, although \nlong delays in diagnosis occurred in some patients. Diminished vibratory \nsensation and proprioception in the lower extremities were the most common \nobjective findings. A wide variety of neurologic symptoms and signs were \nencountered, however, including ataxia, loss of cutaneous sensation, muscle \nweakness, diminished or hyperactive reflexes, spasticity, urinary or fecal \nincontinence, orthostatic hypotension, loss of vision, dementia, psychoses, and \ndisturbances of mood. Multiple neurologic syndromes were often seen in a single \npatient. In 42 (27.4%) of the 153 episodes, the hematocrit was normal, and in 31 \n(23.0%), the mean corpuscular volume was normal. Neutropenia and \nthrombocytopenia were unusual even in anemic patients. In nonanemic patients in \nwhom diagnosis was delayed, neurologic progression frequently occurred although \nthe hematocrit remained normal. In 27 episodes, the serum cobalamin \nconcentration was only moderately decreased (in the range of 100-200 pg/ml) and \nin 2 the serum level was normal. Neurologic impairment, as assessed by a \nquantitative severity score, was judged to be mild in 99 episodes, moderate in \n39 and severe in 15. Severity of neurologic dysfunction before treatment was \nclearly related to the duration of symptoms prior to diagnosis. In addition, the \nhematocrit correlated significantly with severity, independent of the longer \nduration of symptoms in nonanemic patients. Four patients experienced transient \nneurologic exacerbations soon after beginning treatment with cyanocobalamin, \nwith subsequent recovery. Followup evaluation was adequate to assess the \nneurologic response to vitamin B12 therapy in 121 episodes. All patients \nresponded, and in 57 (47.1%), recovery was complete, with no remaining symptoms \nor findings on examination. The severity score was reduced by 50% or greater \nafter treatment in 91% of the episodes. Residual long-term moderate or severe \nneurologic disability was noted following only 7 (6.3%) episodes. The extent of \nneurologic involvement after treatment was strongly related to that before \ntherapy as well as to the duration of symptoms. The percent improvement over \nbaseline neurologic status after treatment was inversely related to duration of \nsymptoms and hematocrit. Some evidence of response was always seen during the \nfirst 3 months of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)",
"The incidence of neurologic complications from bariatric surgery is rising with \nthe prevalence of obesity and the increasing number of bariatric surgeries. We \nreport a 25-year-old woman who developed subacute progressive weakness and \nareflexia followed by confusion, ophthalmoplegia, and nystagmus following \nbariatric surgery. While the differential of generalized weakness with altered \nmental status is broad, vitamin deficiency should be routinely suspected after \nbariatric surgery to prevent permanent neurological injury. Multifocal \nneurological dysfunction in our patient represented beriberi and Wernicke's \nencephalopathy related to vitamin B1 deficiency.",
"Although malabsorption is generally considered to be a gastrointestinal problem, \nthe effects of malabsorption extend far beyond the gastrointestinal tract and \ncan include neurologic dysfunction. Malabsorption may occur by a variety of \nmechanisms, both genetic and acquired, that interfere with the absorption of \nbasic nutrients, vitamins, minerals, and trace elements. Disorders that \ninterfere with fat absorption can lead to neurologic dysfunction as a \nconsequence of associated impairment of fat-soluble vitamin absorption. Thus, \nindividuals with genetic vitamin E deficiency and the familial \nhypocholesterolemias may develop symptoms of peripheral neuropathy, cerebellar \nataxia, and other neurologic signs and symptoms. Disease processes that damage \nthe enteric mucosa and produce malabsorption can trigger neurologic dysfunction \nboth by immune-related processes, as in celiac disease, and by impairing \nabsorption of essential vitamins and other nutrients, as in tropical sprue. \nDeficiencies of water-soluble vitamins, such as thiamine and niacin, can also \ndevelop in the setting of malabsorption and lead to neurologic dysfunction. \nNeurologists are aware of the neurologic damage that copper excess can cause in \nWilson's disease, but copper deficiency due to malabsorption can also produce \nneurologic dysfunction in the form of myelopathy. It is vitally important for \nneurologists to be aware of the potential for malabsorptive processes to produce \nneurologic dysfunction, because effective treatment for such disorders is often \navailable.",
"The activities of the red blood cell enzymes transketolase, glutathione \nreductase, and glutamic oxaloacetate transaminase were measured with and without \nin vitro addition of their respective coenzyme components thiamine, riboflavin, \nand pyridoxine in a group of patients with neurological disorders which may have \nbeen caused by malnutrition, intestinal malabsorption, hepatic failure or \nneoplasms arising outside the nervous system. The incidence of thiamine \ndeficiency was 31%, of riboflavin deficiency 22% and of pyridoxine deficiency \n6%. Alcoholics in particular suffered from deficiencies of vitamin B 1, and B 2. \nThere was a correlation of vitamin B 1 and B 2 deficiency and signs of a \ncerebellar and/or brainstem lesion. The most frequent symptoms in this \nconnection were gait disturbances and oculomotor signs like spontaneous and gaze \nnystagmus, disturbed eye tracking, diminished optokinetic nystagmus, decreased \nability to suppress vestibular nystagmus by fixation. These signs hardly ever \noccurred in alcoholic patients who showed no deficiency of vitamin B 1, B 2 or B \n6. Whenever they do appear, a vitamin B supplementation has to be performed in \norder to prevent the manifestation of Wernicke's encephalopathy, cerebral or \ncerebellar atrophy. Alcoholics showed the same incidence of polyneuropathy, \nwhether they suffered from a deficiency of B vitamins or not. Deficiencies of \nvitamin B 1, B 2 or B 6 were also found in patients with intestinal \nmalabsorption and polyneuropathy, diabetic polyneuropathy, optic atrophy, \nmyelopathy and cerebellar ataxia of unknown etiology, neurological \nmanifestations of neoplasms arising outside the nervous system, B 12 \nmyeloencephalopathy and Thévenard's syndrome.",
"Vitamin B12 deficiency is rare in children, with nonspecific symptoms including \nfailure to thrive, vomiting, anorexia, and neurologic changes with or without \nhematologic disturbances. The neuropathy can be severe and irreversible. We \nreport four cases of children with B12 deficiency secondary to adult type \npernicious anemia, a presumed transport protein abnormality, and a metabolic \ndefect. All demonstrated neurologic compromise that improved after initiation of \nB12 therapy. Hematologic manifestations may be preceded by constitutional, \ngastrointestinal, or neurologic changes, and must raise concern for B12 \ndeficiency. Therapy should be initiated promptly in this setting to prevent \nirreversible neuropathy.",
"Vitamin B12 deficiency is a common cause of neuropsychiatric symptoms in elderly \npersons. Malabsorption accounts for the majority of cases. Vitamin B12 \ndeficiency has been associated with neurologic, cognitive, psychotic, and mood \nsymptoms, as well as treatment-resistance. Clinician awareness should be raised \nto accurately diagnose and treat early deficiencies to prevent irreversible \nstructural brain damage, because current practice can be ineffective at \nidentifying cases leading to neuropsychiatric sequelae. This clinical review \nfocuses on important aspects of the recognition and treatment of vitamin B12 \ndeficiency and neuropsychiatric manifestations of this preventable illness in \nelderly patients.",
"Nearly two thirds of American adults are either overweight or obese. \nAccordingly, bariatric surgery experienced explosive growth during the past \ndecade. Current estimates place the worldwide volume of bariatric procedures at \ngreater than 300,000 cases annually. Micronutrient deficiencies are \nwell-described following bariatric surgery, and they may present with \ndevastating and sometimes irreversible neurologic manifestations. Clinical \nsymptoms range from peripheral neuropathy to encephalopathy, and are most \ncommonly caused by thiamine, copper, and B(12) deficiencies.",
"BACKGROUND: Vitamin B12 (cobalamin, cbl) deficiency in children is rare and may \noccurs in exclusively breast fed infants of mothers on vegetarian or vegan diet \nwith lack of appropriate supplementation. The clinical manifestation of vitamin \nB12 deficiency include neurological disorders, megaloblastic anemia and failure \nto thrive. Routine and commonly used laboratory tests such as cell blood count \n(CBC) or serum vitamin B12 level are sufficient for appropriate diagnosis. \nTypical therapy is based on intramuscular cobalamin injections. Early diagnosis \nand early onset of treatment are crucial factors for long-term prognosis of \npatients as the duration of deficiency may be correlated with the development of \nlong lasting changes in the nervous system. The purpose of this article is to \npresent influence of maternal vitamin B12 deficiency as a cause of infant \npsychomotor retardation.\nCASE PRESENTATION: We report the case of a 7 months old girl whose parents \nsought medical advice due to pathological somnolence and developmental \nregression of their daughter with onset approximately 2 months prior to the \nvisit. Following several diagnostic tests it was determined that the infant's \nsymptoms were due to vitamin B12 deficiency which was secondary to the mother's \nlatent Addison-Biermer disease. Apart from neurological symptoms the infant also \nshowed megaloblastic anemia which is typical to cobalamin deficiencies. \nIntramuscular vitamin B12 supplementation resulted in instant improvement of the \npatient's general condition and blood morphology. Unfortunately, psychological \nexamination indicated long-term psychomotor retardation due to delayed diagnosis \nof B12 deficiency.\nCONCLUSIONS: Vitamin B12 levels should be considered during differential \ndiagnosis of neurological symptoms in exclusively breast-fed infants especially \nif they co-exist with megaloblastic anemia and psychomotor retardation.",
"Vitamin E is one of the most important lipid-soluble antioxidant nutrients. \nSevere vitamin E deficiency can have a profound effect on the central nervous \nsystem. Cystic fibrosis, chronic cholestatic liver disease, \nabetalipoproteinemia, short bowel syndrome, isolated vitamin E deficiency \nsyndrome and other malabsorption syndromes all may cause varying degrees of \nneurologic deficits due to related vitamin deficiencies. The classic \nabnormalities in vitamin E deficiency progress from hyporeflexia, ataxia, \nlimitations in upward gaze and strabismus to long-tract defects, profound muscle \nweakness and visual field constriction. Patients with severe, prolonged \ndeficiency may develop complete blindness, dementia and cardiac arrhythmias. \nTreatment must be tailored to the underlying cause of vitamin E deficiency and \nmay include oral or parenteral vitamin supplementation. The more advanced the \ndeficits, the more limited the response to therapy. Therefore, a good neurologic \nexamination and periodic serum vitamin E levels are essential in patients at \nrisk of vitamin E deficiency.",
"It is well known that the neurologic manifestations of vitamin B12 deficiency \ncan occur in the absence of anemia. The authors recently observed two elderly \npatients who presented to a chronic care institution with the diagnosis of \ndementia, and in both individuals low serum B12 levels were found in conjunction \nwith abnormal Schilling tests. In neither of these two patients was there anemia \nor macrocytosis. After receiving parenteral B12 injections there was improvement \nnoted in cognitive functions as well as in activities of daily living. The \nauthors are reporting these patients to alert clinicians to the fact that \npernicious anemia in the elderly can first present with low serum B12 levels and \nneurologic abnormalities in the absence of anemia or macrocytosis.",
"BACKGROUND: Vision loss resulting from thiamine deficiency is a recognized \ncomplication of bariatric surgery. Most patients with such vision loss have \nWernicke encephalopathy with characteristic changes seen on neuroimaging. Other \npatients may have retinal hemorrhages, optic disc edema, and peripheral \nneuropathy without Wernicke encephalopathy. The risk for thiamine deficiency is \npotentiated by the presence of prolonged vomiting.\nCASE REPORT: A 37-year-old female presented with abrupt onset of vision loss and \nperipheral neuropathy following bariatric surgery. She had a history of \nprolonged vomiting postoperatively. Examination of the posterior segment of the \neye revealed optic disc edema and large retinal hemorrhages bilaterally. \nMetabolic workup demonstrated thiamine deficiency. She responded quickly to \nparenteral thiamine therapy with recovery of normal vision and resolution of \nophthalmologic findings.\nCONCLUSION: Patients who undergo bariatric surgery and have a thiamine \ndeficiency can present with visual symptoms and ophthalmologic findings only \nvisible by fundoscopy prior to developing more severe and potentially \nirreversible complications from the vitamin deficiency. Early detection of \nintraocular changes resulting from thiamine deficiency and initiation of therapy \ncould prevent more devastating neurologic manifestations. Our case supports the \nconsideration of a prospective study aimed at determining the true incidence of \nocular and visual changes such as retinal hemorrhage, optic disc edema, and \nperipapillary telangiectasia in patients following bariatric surgery.",
"BACKGROUND: Nutritional visual defects are apparently uncommon nowadays in \ndeveloped nations. Retinal change-related visual defects caused by \nhypovitaminoses may be underdiagnosed.\nAIM OF THE STUDY: To investigate the retinal structural and functional changes \nin a patient with multivitamin deficiency before and during vitamin \nsupplementation.\nMETHODS: A 51-year-old female had been on vegetarian diet as a child, and on \nrestrict vegan diet during the last 2 years, developing severe bilateral \ndeterioration of visual function and polyneuropathy. Blood test revealed low \nlevels of vitamin A, B6 and D. The patient underwent examinations with optical \ncoherence tomography (OCT), computerized visual field examination (VF), \nelectroretinography (ERG), visual evoked potentials (VEP) and neurography before \nand after vitamin supplementation.\nRESULTS: Visual acuity (VA) was 20/1000 and VF examination showed central \nscotoma in both eyes. Color vision was significantly affected. Full-field ERG \nshowed normal rod and cone function, but a clearly reduced central peak was \nregistered in multifocal ERG (mf-ERG), indicating impaired fovea function. VEP \nshowed delayed latency and low amplitude of P100 in both eyes. Neurography \nshowed sensory polyneuropathy. OCT showed significant thinning of macular \nganglion cell plus inner plexiform layer (GCIPL) with rapid progression. Retinal \nnerve fiber layer (RNFL) was preserved and normal, which is in contrast to \nneuroinflammatory conditions. After 2.5 years of multivitamin supplementation, \nthe visual functions were improved. GCIPL thickness was stable without further \ndeterioration.\nCONCLUSIONS: Multivitamin deficiency results in progressive thinning of GCIPL \nwith severe visual deterioration. In contrast to neuroinflammation, RNFL is \npreserved and normal. Stabilized GCIPL during vitamin supplementation was \nassociated with improved visual function. OCT provides a sensitive and objective \nmeasure for differential diagnosis, monitoring retinal change and response to \ntherapy.",
"BACKGROUND: Vitamin B12 deficiency is often diagnosed with hematological \nmanifestations of megaloblastic macrocytic anemia, which is usually the initial \npresentation. Neurological symptoms are often considered to be late \nmanifestations and usually occur after the onset of anemia. Sub acute combined \ncord degeneration, which is a rare cause of myelopathy is however the commonest \nneurological manifestation of vitamin B12 deficiency.\nCASE PRESENTATION: We present a case of a 66 year old Sinhalese Sri Lankan \nfemale, who is a strict vegetarian, presenting with one month's history \nsuggestive of Sub-acute combined cord degeneration in the absence of \nhaematological manifestations of anaemia. Her Serum B12 levels were \nsignificantly low, after which she was treated with hydroxycobalamine \nsupplementation, showing marked clinical improvement of symptoms, with \nnormalization of serum B12 levels. Hence, the diagnosis of vitamin B12 \ndeficiency was confirmed retrospectively.\nCONCLUSION: Vitamin B12 deficiency could rarely present with neurological \nmanifestations in the absence of anaemia. Therefore a high index of suspicion is \nnecessary for the early diagnosis and prompt treatment in order to reverse \nneurological manifestations, as the response to treatment is inversely \nproportionate to the severity and duration of the disease.",
"Long lists of psychiatric illness or symptoms have been documented to be caused \nby vitamin B12 deficiency. We describe an atypical case of a young adult who \npresented with predominant negative symptoms followed by neurological symptoms \nconsistent with vitamin B12 deficiency. The symptoms showed complete remission \nafter vitamin B12 supplementation. The uniqueness of this case is that vitamin \nB12 deficiency presented with predominant negative symptoms without other \npsychotic and manic symptoms, which has not been reported previously.",
"Jitteriness and tremors in the newborn period typically precipitate an \nextensive, invasive, and expensive search for the etiology. Vitamin D deficiency \nhas not been historically included in the differential of tremors. We report a \nshivering, jittery newborn who was subjected to a battery of testing, with the \nonly biochemical abnormality being vitamin D deficiency. A second case had chin \ntremors and vitamin D deficiency. Review of our patients suggests that shudders, \nshivers, jitteriness, or tremors may be the earliest sign of vitamin D \ndeficiency in the newborn. Neonates who present with these signs should be \ninvestigated for vitamin D deficiency.",
"Publisher: El déficit de vitamina B12 es una de las complicaciones más \nimportantes que puede producir el vegetarianismo. Los lactantes hijos de madres \nvegetarianas tienen riesgo aumentado de deficiencia y de presentar compromiso \nneurológico irreversible si esta no se identifica y corrige adecuadamente. Se \ndescribe el caso de un lactante de un mes y veinte días que consultó por \nepisodios paroxísticos de mecanismo epileptógeno, en el cual los estudios \ncomplementarios permitieron identificar un déficit de vitamina B12 como causa de \nestos. Tras la confirmación diagnóstica, se instauró el tratamiento con vitamina \nB12 intramuscular, con remisión completa de los síntomas, buena evolución \nposterior y desarrollo psicomotor sin alteraciones. Teniendo en cuenta las \ntendencias alimentarias actuales, es necesario incorporar, en la práctica \nclínica habitual, la anamnesis nutricional materna detallada para detectar \nprecozmente el riesgo de déficit de esta vitamina y prevenirlo.",
"Hyperemesis gravidarum is a complication of pregnancy associated with severe \nnausea and vomiting that can lead to fluid-electrolyte imbalances and \nnutritional deficiencies. Wernicke's encephalopathy is a neurologic \nmanifestation of acute thiamine (vitamin B1) deficiency. We describe a case of \nhyperemesis gravidarum presenting with gait ataxia and nystagmus which led to a \ndiagnosis of Wernicke's encephalopathy.",
"Vitamin B(12) deficiency (B(12)D) has a wide variety of neurological symptoms \nand signs. However, cerebellar dysfunction and cranial neuropathies other than \noptic neuropathy have been rarely reported. Herein, we describe two cases of \nunusual neurological manifestations of B(12)D. One patient showed prominent \nhoarseness with vocal cord paralysis, myelopathy, and peripheral neuropathy. The \nother had gait disturbance, lateral gaze limitation and cerebellar dysfunction \nin addition to the typical manifestations of subacute combined degeneration. \nVitamin B(12) deficiency can rarely affect cerebellum and cranial nerves other \nthan optic nerve.",
"The review discusses thesteps of vitamin B12 metabolism and its role in \nmaintaining of neurological functions. The term \"vitamin B12 (cobalamin)\" refers \nto several substances (cobalamins) of a very similar structure. Cobalamin enters \nthe body with animal products. On the peripherу cobalamin circulates only in \nbinding with proteins transcobalamin I and II (complex cobalamin-transcobalamin \nII is designated as \"holotranscobalamin\"). Holotranscobalamin is absorbed by \ndifferent cells, whereas transcobalamin I-binded vitamin B12 - only by liver and \nkidneys. Two forms of cobalamin were identified as coenzymes of cellular \nreactions which are methylcobalamin (in cytoplasm) and hydroxyadenosylcobalamin \n(in mitochondria). The main causes of cobalamin deficiency are related to \ninadequate intake of animal products, autoimmune gastritis, pancreatic \ninsufficiency, terminal ileum disease, syndrome of intestinal bacterial \novergrowth. Relative deficiency may be seen in excessive binding of vitamin B12 \nto transcobalamin I. Cobalamin deficiency most significantly affects functions \nof blood, nervous system and inflammatory response. Anemia occurs in 13-15% of \ncases; macrocytosis is an early sign. The average size of neutrophils and \nmonocytes is the most sensitive marker of megaloblastic hematopoiesis. The \ndemands in vitamin B12 are particularly high in nervous tissue. Hypovitaminosis \nis accompanied by pathological lesions both in white and gray brain matter. \nSeveral types of neurological manifestations are described: subacute combined \ndegeneration of spinal cord (funicular myelinosis), sensomotor polyneuropathy, \noptic nerve neuropathy, cognitive disorders. The whole range of neuropsychiatric \ndisorders with vitamin B12 deficiency has not been studied well enough. Due to \ncertain diagnostic difficulties they are often regarded as \"cryptogenic\", \n\"reactive\", \"vascular» origin. Normal or decreased total plasma cobalamin level \ncould not a reliable marker of vitamin deficiency. In difficult cases the \ncontent of holotranscobalamin, methylmalonic acid / homocysteine, and folate in \nthe blood serum should be investigated besides carefully analysis of clinical \nmanifestations.",
"Although cobalamin (vitamin B12) deficiency was described over a century ago, it \nis still difficult to establish the correct diagnosis and prescribe the right \ntreatment. Symptoms related to vitamin B12 deficiency may be diverse and vary \nfrom neurologic to psychiatric. A number of individuals with vitamin B12 \ndeficiency may present with the classic megaloblastic anemia. In clinical \npractice, many cases of vitamin B12 deficiency are overlooked or sometimes even \nmisdiagnosed. In this review, we describe the heterogeneous disease spectrum of \npatients with vitamin B12 deficiency in whom the diagnosis was either based on \nlow serum B12 levels, elevated biomarkers like methylmalonic acid and/or \nhomocysteine, or the improvement of clinical symptoms after the institution of \nparenteral vitamin B12 therapy. We discuss the possible clinical signs and \nsymptoms of patients with B12 deficiency and the various pitfalls of diagnosis \nand treatment.",
"Alzheimer's disease (AD) starts with memory impairments that can be observed \nbefore the appearance of significant neuropathology; thus, identifying \nmechanisms to stop AD progression is an urgent priority. Epidemiological and \nclinical data show that the consequences of vitamin D deficiency are relevant to \ndisease risk and can be observed in the progression of many diseases, especially \nAD, whereas higher serum levels of vitamin D are associated with better \ncognitive test performance. However, the potential therapeutic strategy and \nunderlying mechanisms of vitamin D supplementation against AD still need to be \nfurther investigated. In the present study, we found that 3xTg-AD mice with \nvitamin D supplementation exhibited an increase in serum vitamin D \nconcentrations and improved cognition. We measured serum vitamin D binding \nprotein (VDBP) concentrations and found that serum VDBP levels were increased in \n3xTg-AD mice compared to B6129S control mice, but there was no significant \ndifference between control- and vitamin D-treated 3xTg-AD groups. The vitamin \nD-mediated memory improvement may be accompanied by the suppression of increased \nhippocampal collapsin response mediator protein-2 (CRMP2) phosphorylation, and \nthe restoration of CRMP2 phosphorylation by okadaic acid (OA) could abolish the \nbeneficial effects of vitamin D. In addition, we found that CRMP2 was associated \nwith NR2B and PSD-95 in 3xTg-AD mice with vitamin D supplementation. This \nCRMP2-NR2B interaction could be disrupted by a TAT-CBD3 peptide or OA, leading \nto attenuated memory protection in vitamin D-treated 3xTg-AD mice. Therefore, \nCRMP2 may be involved in vitamin D-mediated memory improvement in AD.",
"Optimal functioning of the central and peripheral nervous system is dependent on \na constant supply of essential nutrients. Nutritional deficiencies of thiamine \nand niacin, rarely vitamin B (12), and possibly folate can cause a wide range of \nneuropsychiatric manifestations. Neurologic manifestations associated with these \ndeficiency states are the focus of this review. The preventable and potentially \ntreatable nature of these disorders makes this an important subject. Prognosis \ndepends on prompt recognition and institution of appropriate therapy.",
"RATIONALE: There have been a few reported cases of subacute combined \ndegeneration (SCD) associated with vitamin E deficiency, but the period of \nintestinal malabsorption was more than several years. We present a rare case of \nacute onset SCD that occurred in a relatively short period of several weeks with \nvitamin E deficiency related to small bowel obstruction.\nPATIENT CONCERNS: A 50-year-old woman had abdominal pain. A small bowel \nobstruction was suspected and conservative treatment was performed. She \nunderwent bowel surgery after 2 weeks without any improvement. Following the \noperation, she was in a state of reduced consciousness. She was treated in an \nintensive care unit. Her consciousness level gradually recovered to alert in a \nweek, but other symptoms such as ataxia, weakness on limbs, severe dysarthria, \nand dysphagia occurred. Since then, she had spent nearly 6 weeks in a bed-ridden \nstate without improving.\nDIAGNOSIS: SCD associated with vitamin E deficiency was confirmed by laboratory \ninvestigations, electrophysiologic test, and whole spine magnetic resonance \nimaging scans.\nINTERVENTIONS: For vitamin E supplementation, she was administered a dose of \n1200 mg/d. Physical therapy was focused on strengthening exercise, balance, and \nwalker gait training. Occupational therapy was focused on activities of daily \nliving training and dysphagia rehabilitation.\nOUTCOMES: After 6 weeks, her muscle strengths and functional level were \nsubstantially improved. The vitamin E level was recovered to normal range.\nLESSONS: This case suggests that if neurological symptoms occur in patients with \nintestinal obstruction, clinicians need to consider a deficiency of \nmicronutrients such as vitamin E and vitamin B12. Patients with short clinical \ncourses suffer less neurological damage and achieve faster recovery.",
"Vitamin E malabsorption and deficiency during chronic childhood cholestasis has \nbeen associated with a progressive ataxic neurologic syndrome. Hyporeflexia, the \nfirst sign of neurologic dysfunction, may begin prior to age 2 years, but severe \nsymptoms do not develop until age 5 to 10 years. To establish the age of onset \nof neuropathologic lesions, we prospectively evaluated four young children with \nsevere cholestasis. Malabsorption and deficiency of vitamin E were documented by \nlow serum vitamin E concentrations, low serum vitamin E to total serum lipids \nratios, elevated hydrogen peroxide hemolysis, and impaired absorption of a \npharmacologic dose of alpha-tocopherol. Abnormal neurologic findings in two \npatients were limited to areflexia, ptosis, mild truncal ataxia, and hypotonia; \ntwo patients had minimal signs of neurologic dysfunction. Sural nerve histology \nat age 6 to 25 months revealed a degenerative axonopathy involving large-caliber \nmyelinated fibers, but without quantitative axonal loss. Muscle histology and \nhistochemistry tests yielded normal results. Our study suggests that neurologic \ninjury may occur during the first two years of life in vitamin E-deficient \nchildren with cholestatic hepatobiliary disease, obligating aggressive attempts \nat correcting this deficiency state at a very young age.",
"Neuropathies associated with nutritional deficiencies are routinely encountered \nby the practicing neurologist. Although these neuropathies assume different \npatterns, most are length-dependent, sensory axonopathies. Cobalamin deficiency \nneuropathy is the exception, often presenting with a non-length-dependent \nsensory neuropathy. Patients with cobalamin and copper deficiency neuropathy \ncharacteristically have concomitant myelopathy, whereas vitamin E deficiency is \nuniquely associated with a spinocerebellar syndrome. In contrast to those \nnutrients for which deficiencies produce neuropathies, pyridoxine toxicity \nresults in a non-length-dependent sensory neuronopathy. Deficiencies occur in \nthe context of malnutrition, malabsorption, increased nutrient loss (such as \nwith dialysis), autoimmune conditions such as pernicious anemia, and with \ncertain drugs that inhibit nutrient absorption. When promptly identified, \ntherapeutic nutrient supplementation may result in stabilization or improvement \nof these neuropathies.",
"Isolated vitamin B12 deficiency is a common condition in elderly patients but \nuncommon in patients younger than 30 years, with an average age of onset between \n60 and 70 years. This is because the dietary cobalamin, which is normally split \nby enzymes in meat in the presence of hydrochloric acid and pepsin in the \nstomach, is not released in the stomachs of elderly patients, usually due to \nachlorhydria. Although the body may be unable to release cobalamin it does \nretain the ability to absorb vitamin B12 in its crystalline form, which is \npresent in multivitamin preparations. Other causes are due to drugs that \nsuppress gastric acid production. Neurological signs of vitamin B12 deficiency \ncan occur in patients with a normal haematocrit and red cell indices. They \ninclude paresthesia, loss of sensation and strength in the limbs, and ataxia. \nReflexes may be slowed down or increased. Romberg and Babinsky signs may be \npositive, and vibration and position sensitivity often decreases. Behavoural \ndisorders range from irritability and memory loss to severe dementia. The \nsymptoms often do not fully respond to treatment. A case is presented of an \nisolated vitamin B12 deficiency in 27 year-old female patient who was seen in \nprimary health care. During anamnesis she mentioned low back pain, to which she \nattributed the loss of strength and tenderness in the right side of the body, as \nwell as the slow and progressive onset of accompanied headache for the previous \n4 days.",
"Children deficient in vitamin E have various neurologic symptoms. 2 cases \nrepresenting different mechanisms of this vitamin deficiency are reported. A \n15-year-old boy with fat malabsorption due to cystic fibrosis who was diagnosed \nas being vitamin E deficient (< 0.5 mg/l), had typical neuropathies. On the \nother hand, a 12-year-old Beduin girl had isolated vitamin E deficiency, as well \nas neurological symptoms suggestive of Friedrich's ataxia. Vitamin E \nsupplementation by intramuscular injection in the first case and per os in the \nsecond led to significant improvement in neurological symptoms.",
"Ataxia with vitamin E deficiency is an autosomal recessive condition associated \nwith a defect in the a-tocopherol transfer protein. Clinically it manifests as a \nprogressive ataxia with a phenotype resembling that of Friedreich's ataxia. \nThere is some evidence that progression of neurological symptoms is prevented by \nvitamin E therapy. A patient is described who was given a clinical diagnosis of \nFriedreich's ataxia. Molecular genetic analysis showed the absence of the \nfrataxin gene expansion. Subsequent vitamin E assay showed deficiency and a \ndiagnosis of ataxia with vitamin E deficiency was made. It is recommended that \nall patients with ataxia of unknown cause should have vitamin E deficiency \nexcluded. When a diagnosis of Friedreich's ataxia is considered patients should \nhave frataxin analysis in addition. Further, neurologists should be aware that \nataxia with vitamin E deficiency may present as \"mutation negative\" Friedreich's \nataxia."
] | nan |
6053ba5b94d57fd879000017 | [
31785606
] | train | Which was the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA)? | factoid | FTY720 (Fingolimod) was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. | 7 | [
"FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist \nthat exerts strong anti-inflammatory effects and was approved as the first oral \ndrug for the treatment of multiple sclerosis by the US Food and Drug \nAdministration (FDA) in 2010. FTY720 is mainly associated with unique functional \n\"antagonist\" and \"agonist\" mechanisms. The functional antagonistic mechanism is \nmediated by the transient down-regulation and degradation of S1P receptors on \nlymphocytes, which prevents lymphocytes from entering the blood stream from the \nlymph node. This subsequently results in the development of lymphopenia and \nreduces lymphocytic inflammation. Functional agonistic mechanisms are executed \nthrough S1P receptors expressed on the surface of various cells including \nneurons, astrocytes, microglia, and blood vessel endothelial cells. These \nfunctions might play important roles in regulating anti-apoptotic systems, \nmodulating brain immune and phagocytic activities, preserving the \nBlood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. \nRecently, FTY720 have shown receptor-independent effects, including \nintracellular target bindings and epigenetic modulations. Many researchers have \nrecognized the positive effects of FTY720 and launched basic and clinical \nexperiments to test the use of this agent against stroke. Although the mechanism \nof FTY720 has not been fully elucidated, its efficacy against cerebral stroke is \nbecoming clear, not only in animal models, but also in ischemic stroke patients \nthrough clinical trials. In this article, we review the data obtained from \nlaboratory findings and preliminary clinical trials using FTY720 for stroke \ntreatment."
] | nan |
5c897555d558e5f232000009 | [
30089698
] | train | Which was the first adeno-associated virus vector gene therapy product approved in the United States? | factoid | The first adeno-associated virus vector gene therapy product in the United States was Luxturna. | Luxturna | [
"Recent clinical trials have demonstrated the potential of adeno-associated virus \n(AAV)-based vectors for treating rare diseases. However, significant barriers \nremain for the translation of these vectors into widely available therapies. In \nparticular, exposure to the AAV capsid can generate an immune response of \nneutralizing antibodies. One approach to overcome this response is to map the \nAAV-specific neutralizing epitopes and rationally design an AAV capsid able to \nevade neutralization. To accomplish this, we isolated a monoclonal antibody \nagainst AAV9 following immunization of BALB/c mice and hybridoma screening. This \nantibody, PAV9.1, is specific for intact AAV9 capsids and has a high \nneutralizing titer of >1:160,000. We used cryo-electron microscopy to \nreconstruct PAV9.1 in complex with AAV9. We then mapped its epitope to the \n3-fold axis of symmetry on the capsid, specifically to residues 496-NNN-498 and \n588-QAQAQT-592. Capsid mutagenesis demonstrated that even a single amino acid \nsubstitution within this epitope markedly reduced binding and neutralization by \nPAV9.1. In addition, in vivo studies showed that mutations in the PAV9.1 epitope \nconferred a \"liver-detargeting\" phenotype to the mutant vectors, unlike AAV9, \nindicating that the residues involved in PAV9.1 interactions are also \nresponsible for AAV9 tropism. However, we observed minimal changes in binding \nand neutralizing titer when we tested these mutant vectors for evasion of \npolyclonal sera from mice, macaques, or humans previously exposed to AAV. Taken \ntogether, these studies demonstrate the complexity of incorporating mapped \nneutralizing epitopes and previously identified functional motifs into the \ndesign of novel capsids able to evade immune response.IMPORTANCE Gene therapy \nutilizing viral vectors has experienced recent success, culminating in U.S. Food \nand Drug Administration approval of the first adeno-associated virus vector gene \ntherapy product in the United States: Luxturna for inherited retinal dystrophy. \nHowever, application of this approach to other tissues faces significant \nbarriers. One challenge is the immune response to viral infection or vector \nadministration, precluding patients from receiving an initial or readministered \ndose of vector, respectively. Here, we mapped the epitope of a novel \nneutralizing antibody generated in response to this viral vector to design a \nnext-generation capsid to evade immune responses. Epitope-based mutations in the \ncapsid interfered with the binding and neutralizing ability of the antibody but \nnot when tested against polyclonal samples from various sources. Our results \nsuggest that targeted mutation of a greater breadth of neutralizing epitopes \nwill be required to evade the repertoire of neutralizing antibodies responsible \nfor blocking viral vector transduction."
] | nan |
5e7641a0c6a8763d23000011 | [
29018300
] | train | Which was the first cholera vaccine approved in the US? | factoid | Vaxchora is the first vaccine approved by the Food and Drug Administration for the prophylaxis of cholera infection. | Vaxchora | [
"Vaxchora is the first vaccine approved by the Food and Drug Administration for \nthe prophylaxis of cholera infection. Cholera, a potentially life-threatening \nbacterial infection that occurs in the intestines and causes severe diarrhea and \ndehydration, has a low incidence in the U.S., but a high incidence in Africa, \nSoutheast Asia, and other locations around the world. These areas draw travelers \nfrom the U.S., so cholera can present in patients who return from visits to \nthese regions. Previous means of prophylaxis included the use of doxycycline for \nthe prevention of traveler's diarrhea, but doxycycline is not specific for \ncholera. With the approval of Vaxchora, a live attenuated, single-dose, oral \nsuspension vaccine, travelers can now visit these areas with less chance of \ncontracting the bacterium Vibrio cholerae, which causes cholera infections."
] | nan |
5c8973f3d558e5f232000007 | [
28284702
] | train | Which was the first gene therapy to receive marketing authorization in the European Union? | factoid | The first gene therapy to receive marketing authorization in the European Union was Glybera (alipogene tiparvovec). | Glybera or Alipogene tiparvovec | [
"A good understanding of the natural history of rare genetic lipid disorders is a \npre-requisite for successful patient management. Disease registries have been \nhelpful in this regard. Lipoprotein Lipase Deficiency (LPLD) is a rare, \nautosomal-recessive lipid disorder characterized by severe hypertriglyceridemia \nand a very high risk for recurrent acute pancreatitis, however, only limited \ndata are available on its natural course. Alipogene tiparvovec (Glybera®) is the \nfirst gene therapy to receive Marketing Authorization in the European Union; \nGENIALL (GENetherapy In the MAnagement of Lipoprotein Lipase Deficiency), a \n15-year registry focusing on LPLD was launched in 2014 as part of its Risk \nManagement Plan. The aim of this publication is to introduce the GENIALL \nRegistry within a structured literature review of registries in rare genetic \nlipid disorders. A total of 11 relevant initiatives/registries were identified \n(homozygous Familial Hypercholesterolemia (hoFH) [n = 5]; LPLD [n = 1]; \nLysosomal Acid Lipase Deficiency [LALD, n = 1], detection of mutations in \ngenetic lipid disorders [n = 4]). Besides one product registry in hoFH and the \nLALD registry, all other initiatives are local or country-specific. GENIALL is \nthe first global prospective registry in LPLD that will collect physician and \npatient generated data on the natural course of LPLD, as well as long-term \noutcomes of gene therapy.\nCONCLUSION: There is a limited number of international initiatives focusing on \nthe natural course of specific rare genetic lipid disorders. The GENIALL LPLD \nRegistry could be the first step towards a future broader global initiative that \ncollects data related to familial chylomicronemia syndrome and their underlying \ngenetic causes."
] | nan |
5c65897a7c78d69471000006 | [
30360730
] | train | Which was the first mutant IDH2 inhibitor to be approved for patients with acute myeloid leukemia? | factoid | Enasidenib was the first mutant IDH2 inhibitor to be approved for the treatment of refractory and relapsed acute myeloid leukemia. | Enasidenib | [
"BACKGROUND: Acute myeloid leukemia is the collective name for different types of \nleukemias of myeloid origin affecting blood and bone marrow. The overproduction \nof immature myeloblasts (white blood cells) is the characteristic feature of \nAML, thus flooding the bone marrow and reducing its capacity to produce normal \nblood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly \nknown as AG-221 which is being marketed under the name Idhifa to treat R/R AML \nwith IDH2 mutation. The present review depicts the broad profile of enasidenib \nincluding various aspects of chemistry, preclinical, clinical studies, \npharmacokinetics, mode of action and toxicity studies.\nMETHODS: Various reports and research articles have been referred to summarize \ndifferent aspects related to chemistry and pharmacokinetics of enasidenib. \nClinical data was collected from various recently published clinical reports \nincluding clinical trial outcomes.\nRESULT: The various findings of enasidenib revealed that it has been designed to \nallosterically inhibit mutated IDH2 to treat R/R AML patients. It has also \npresented good safety and efficacy profile along with 9.3 months overall \nsurvival rates of patients in which disease has relapsed. The drug is still \nunder study either in combination or solely to treat hematological malignancies. \nMolecular modeling studies revealed that enasidenib binds to its target through \nhydrophobic interaction and hydrogen bonding inside the binding pocket. \nEnasidenib is found to be associated with certain adverse effects like elevated \nbilirubin level, diarrhea, differentiation syndrome, decreased potassium and \ncalcium levels, etc.\nCONCLUSION: Enasidenib or AG-221was introduced by FDA as an anticancer agent \nwhich was developed as a first in class, a selective allosteric inhibitor of the \ntumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial \nof Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. \nPhase III trial on the Enasidenib is still under process along with another \ntrial to test its potency against other cell lines. Edasidenib is associated \nwith certain adverse effects, which can be reduced by investigators by designing \nits newer derivatives on the basis of SAR studies. Hence, it may come in the \nlight as a potent lead entity for anticancer treatment in the coming years."
] | nan |
5eb422150d431b5f73000009 | [
25506301,
29556078,
27358863,
28943376,
22722833,
28325876,
30346517,
24391509,
28642936,
27103098,
27056411,
29216381
] | train | Which was the first species in which a de novo gene emergence ("gene birth") was reported? | factoid | New genes can arise through duplication of a pre-existing gene or de novo from non-coding DNA, providing raw material for evolution of new functions in response to a changing environment. A prime example is the independent evolution of antifreeze glycoprotein genes (afgps) in the Arctic codfishes and Antarctic notothenioids to prevent freezing. | the Arctic codfish | [
"Genomes contain a large number of unique genes which have not been found in \nother species. Although the origin of such \"orphan\" genes remains unclear, they \nare thought to be involved in species-specific adaptive processes. Here, we \nanalyzed seven orphan genes (MoSPC1 to MoSPC7) prioritized based on in planta \nexpressed sequence tag data in the rice blast fungus, Magnaporthe oryzae. \nExpression analysis using qRT-PCR confirmed the expression of four genes \n(MoSPC1, MoSPC2, MoSPC3 and MoSPC7) during plant infection. However, individual \ndeletion mutants of these four genes did not differ from the wild-type strain \nfor all phenotypes examined, including pathogenicity. The length, GC contents, \ncodon adaptation index and expression during mycelial growth of the four genes \nsuggest that these genes formed during the evolutionary history of M. oryzae. \nSynteny analyses using closely related fungal species corroborated the notion \nthat these genes evolved de novo in the M. oryzae genome. In this report, we \ndiscuss our inability to detect phenotypic changes in the four deletion mutants. \nBased on these results, the four orphan genes may be products of de novo gene \nbirth processes, and their adaptive potential is in the course of being tested \nfor retention or extinction through natural selection.",
"Accumulating evidence indicates that some protein-coding genes have originated \nde novo from previously non-coding genomic sequences. However, the processes \nunderlying de novo gene birth are still enigmatic. In particular, the appearance \nof a new functional protein seems highly improbable unless there is already a \npool of neutrally evolving peptides that are translated at significant levels \nand that can at some point acquire new functions. Here, we use deep \nribosome-profiling sequencing data, together with proteomics and single \nnucleotide polymorphism information, to search for these peptides. We find \nhundreds of open reading frames that are translated and that show no \nevolutionary conservation or selective constraints. These data suggest that the \ntranslation of these neutrally evolving peptides may be facilitated by the \nchance occurrence of open reading frames with a favourable codon composition. We \nconclude that the pervasive translation of the transcriptome provides plenty of \nmaterial for the evolution of new functional proteins.",
"BACKGROUND: Introns are universal in eukaryotic genomes and play important roles \nin transcriptional regulation, mRNA export to the cytoplasm, nonsense-mediated \ndecay as both a regulatory and a splicing quality control mechanism, R-loop \navoidance, alternative splicing, chromatin structure, and evolution by \nexon-shuffling.\nMETHODS: Sixteen complete fungal genomes were used 13 of which were sequenced \nand annotated by JGI. Ustilago maydis, Cryptococcus neoformans, and Coprinus \ncinereus (also named Coprinopsis cinerea) were from the Broad Institute. Gene \nmodels from JGI-annotated genomes were taken from the GeneCatalog track that \ncontained the best representative gene models. Varying fractions of the \nGeneCatalog were manually curated by external users. For clarity, we used the \nJGI unique database identifier.\nRESULTS: The last common ancestor of eukaryotes (LECA) has an estimated 6.4 \ncoding exons per gene (EPG) and evolved into the diverse eukaryotic life forms, \nwhich is recapitulated by the development of a stem cell. We found a parallel \nbetween the simulated reverse transcriptase (RT)-mediated intron loss and the \ncomparative analysis of 16 fungal genomes that spanned a wide range of intron \ndensity. Although footprints of RT (RTF) were dynamic, relative intron location \n(RIL) to the 5'-end of mRNA faithfully traced RT-mediated intron loss and \nrevealed 7.7 EPG for LECA. The mode of exon length distribution was conserved in \nsimulated intron loss, which was exemplified by the shared mode of 75 nt between \nfungal and Chlamydomonas genomes. The dominant ancient exon length was \ncorroborated by the average exon length of the most intron-rich genes in fungal \ngenomes and consistent with ancient protein modules being ~25 aa. Combined with \nthe conservation of a protein length of 400 aa, the earliest ancestor of \neukaryotes could have 16 EPG. During earlier evolution, Ascomycota's ancestor \nhad significantly more 3'-biased RT-mediated intron loss that was followed by \ndramatic RTF loss. There was a down trend of EPG from more conserved to less \nconserved genes. Moreover, species-specific genes have higher exon-densities, \nshorter exons, and longer introns when compared to genes conserved at the phylum \nlevel. However, intron length in species-specific genes became shorter than that \nof genes conserved in all species after genomes experiencing drastic intron \nloss. The estimated EPG from the most frequent exon length is more than double \nthat from the RIL method.\nCONCLUSIONS: This implies significant intron loss during the very early period \nof eukaryotic evolution. De novo gene-birth contributes to shorter exons, longer \nintrons, and higher exon-density in species-specific genes relative to conserved \ngenes.",
"Taxon-specific de novo protein-coding sequences are thought to be important for \ntaxon-specific environmental adaptation. A recent study revealed that bottlenose \ndolphins acquired a novel isoform of aquaporin 2 generated by alternative \nsplicing (alternative AQP2), which helps dolphins to live in hyperosmotic \nseawater. The AQP2 gene consists of four exons, but the alternative AQP2 gene \nlacks the fourth exon and instead has a longer third exon that includes the \noriginal third exon and a part of the original third intron. Here, we show that \nthe latter half of the third exon of the alternative AQP2 arose from a \nnon-protein-coding sequence. Intact ORF of this de novo sequence is shared not \nby all cetaceans, but only by delphinoids. However, this sequence is \nconservative in all modern cetaceans, implying that this de novo sequence \npotentially plays important roles for marine adaptation in cetaceans.",
"Novel protein-coding genes can arise either through re-organization of \npre-existing genes or de novo. Processes involving re-organization of \npre-existing genes, notably after gene duplication, have been extensively \ndescribed. In contrast, de novo gene birth remains poorly understood, mainly \nbecause translation of sequences devoid of genes, or 'non-genic' sequences, is \nexpected to produce insignificant polypeptides rather than proteins with \nspecific biological functions. Here we formalize an evolutionary model according \nto which functional genes evolve de novo through transitory proto-genes \ngenerated by widespread translational activity in non-genic sequences. Testing \nthis model at the genome scale in Saccharomyces cerevisiae, we detect \ntranslation of hundreds of short species-specific open reading frames (ORFs) \nlocated in non-genic sequences. These translation events seem to provide \nadaptive potential, as suggested by their differential regulation upon stress \nand by signatures of retention by natural selection. In line with our model, we \nestablish that S. cerevisiae ORFs can be placed within an evolutionary continuum \nranging from non-genic sequences to genes. We identify ~1,900 candidate \nproto-genes among S. cerevisiae ORFs and find that de novo gene birth from such \na reservoir may be more prevalent than sporadic gene duplication. Our work \nillustrates that evolution exploits seemingly dispensable sequences to generate \nadaptive functional innovation.",
"RNA-binding proteins (RBPs) control the fate of nearly every transcript in a \ncell. However, no existing approach for studying these posttranscriptional gene \nregulators combines transcriptome-wide throughput and biophysical precision. \nHere, we describe an assay that accomplishes this. Using commonly available \nhardware, we built a customizable, open-source platform that leverages the \ninherent throughput of Illumina technology for direct biophysical measurements. \nWe used the platform to quantitatively measure the binding affinity of the \nprototypical RBP Vts1 for every transcript in the Saccharomyces cerevisiae \ngenome. The scale and precision of these measurements revealed many previously \nunknown features of this well-studied RBP. Our transcribed genome array (TGA) \nassayed both rare and abundant transcripts with equivalent proficiency, \nrevealing hundreds of low-abundance targets missed by previous approaches. These \ntargets regulated diverse biological processes including nutrient sensing and \nthe DNA damage response, and implicated Vts1 in de novo gene \"birth.\" TGA \nprovided single-nucleotide resolution for each binding site and delineated a \nhighly specific sequence and structure motif for Vts1 binding. Changes in \ntranscript levels in vts1Δ cells established the regulatory function of these \nbinding sites. The impact of Vts1 on transcript abundance was largely \nindependent of where it bound within an mRNA, challenging prevailing assumptions \nabout how this RBP drives RNA degradation. TGA thus enables a quantitative \ndescription of the relationship between variant RNA structures, affinity, and in \nvivo phenotype on a transcriptome-wide scale. We anticipate that TGA will \nprovide similarly comprehensive and quantitative insights into the function of \nvirtually any RBP.",
"The evolution of novel protein-coding genes from noncoding regions of the genome \nis one of the most compelling pieces of evidence for genetic innovations in \nnature. One popular approach to identify de novo genes is phylostratigraphy, \nwhich consists of determining the approximate time of origin (age) of a gene \nbased on its distribution along a species phylogeny. Several studies have \nrevealed significant flaws in determining the age of genes, including de novo \ngenes, using phylostratigraphy alone. However, the rate of false positives in de \nnovo gene surveys, based on phylostratigraphy, remains unknown. Here, I \nreanalyze the findings from three studies, two of which identified tens to \nhundreds of rodent-specific de novo genes adopting a phylostratigraphy-centered \napproach. Most putative de novo genes discovered in these investigations are no \nlonger included in recently updated mouse gene sets. Using a combination of \nsynteny information and sequence similarity searches, I show that ∼60% of the \nremaining 381 putative de novo genes share homology with genes from other \nvertebrates, originated through gene duplication, and/or share no synteny \ninformation with nonrodent mammals. These results led to an estimated rate of \n∼12 de novo genes per million years in mouse. Contrary to a previous study \n(Wilson BA, Foy SG, Neme R, Masel J. 2017. Young genes are highly disordered as \npredicted by the preadaptation hypothesis of de novo gene birth. Nat Ecol Evol. \n1:0146), I found no evidence supporting the preadaptation hypothesis of de novo \ngene formation. Nearly half of the de novo genes confirmed in this study are \nwithin older genes, indicating that co-option of preexisting regulatory regions \nand a higher GC content may facilitate the origin of novel genes.",
"The rearrangement of pre-existing genes has long been thought of as the major \nmode of new gene generation. Recently, de novo gene birth from non-genic DNA was \nfound to be an alternative mechanism to generate novel protein-coding genes. \nHowever, its functional role in human disease remains largely unknown. Here we \nshow that NCYM, a cis-antisense gene of the MYCN oncogene, initially thought to \nbe a large non-coding RNA, encodes a de novo evolved protein regulating the \npathogenesis of human cancers, particularly neuroblastoma. The NCYM gene is \nevolutionally conserved only in the taxonomic group containing humans and \nchimpanzees. In primary human neuroblastomas, NCYM is 100% co-amplified and \nco-expressed with MYCN, and NCYM mRNA expression is associated with poor \nclinical outcome. MYCN directly transactivates both NCYM and MYCN mRNA, whereas \nNCYM stabilizes MYCN protein by inhibiting the activity of GSK3β, a kinase that \npromotes MYCN degradation. In contrast to MYCN transgenic mice, neuroblastomas \nin MYCN/NCYM double transgenic mice were frequently accompanied by distant \nmetastases, behavior reminiscent of human neuroblastomas with MYCN \namplification. The NCYM protein also interacts with GSK3β, thereby stabilizing \nthe MYCN protein in the tumors of the MYCN/NCYM double transgenic mice. Thus, \nthese results suggest that GSK3β inhibition by NCYM stabilizes the MYCN protein \nboth in vitro and in vivo. Furthermore, the survival of MYCN transgenic mice \nbearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual \nPI3K/mTOR inhibitor shown to destabilize MYCN via GSK3β activation. In contrast, \ntumors caused in MYCN/NCYM double transgenic mice showed chemo-resistance to the \ndrug. Collectively, our results show that NCYM is the first de novo evolved \nprotein known to act as an oncopromoting factor in human cancer, and suggest \nthat de novo evolved proteins may functionally characterize human disease.",
"The phenomenon of de novo gene birth from junk DNA is surprising, because random \npolypeptides are expected to be toxic. There are two conflicting views about how \nde novo gene birth is nevertheless possible: the continuum hypothesis invokes a \ngradual gene birth process, while the preadaptation hypothesis predicts that \nyoung genes will show extreme levels of gene-like traits. We show that intrinsic \nstructural disorder conforms to the predictions of the preadaptation hypothesis \nand falsifies the continuum hypothesis, with all genes having higher levels than \ntranslated junk DNA, but young genes having the highest level of all. Results \nare robust to homology detection bias, to the non-independence of multiple \nmembers of the same gene family, and to the false positive annotation of \nprotein-coding genes.",
"Sequence similarity tools like Basic Local Alignment Search Tool (BLAST) are \nessential components of many functional genetic, genomic, phylogenetic and \nbioinformatic studies. Many modern analysis pipelines use significant sequence \nsimilarity scores (p- or E-values) and the ranked order of BLAST matches to test \na wide range of hypotheses concerning homology, orthology, the timing of de novo \ngene birth/death and gene family expansion/contraction. Despite significant \ncontrary findings, many of these tests still implicitly assume that stronger or \nhigher-ranked E-value scores imply closer phylogenetic relationships between \nsequences. Here, we demonstrate that even though a general relationship does \nexist between the phylogenetic distance of two sequences and their E-value, \nsignificant and misleading errors occur in both the completeness and the order \nof results under realistic evolutionary scenarios. These results provide \nadditional details to past evidence showing that studies should avoid drawing \ndirect inferences of evolutionary relatedness from measures of sequence \nsimilarity alone, and should instead, where possible, use more rigorous \nphylogeny-based methods.",
"De novo protein-coding gene origination is increasingly recognized as an \nimportant evolutionary mechanism. However, there remains a large amount of \nuncertainty regarding the frequency of these events and the mechanisms and speed \nof gene establishment. Here, we describe a rigorous search for cases of de novo \ngene origination in the great apes. We analyzed annotated proteomes as well as \nfull genomic DNA and transcriptional and translational evidence. It is notable \nthat results vary between database updates due to the fluctuating annotation of \nthese genes. Nonetheless we identified 35 de novo genes: 16 human-specific; 5 \nhuman and chimpanzee specific; and 14 that originated prior to the divergence of \nhuman, chimpanzee, and gorilla and are found in all three genomes. The \ntaxonomically restricted distribution of these genes cannot be explained by loss \nin other lineages. Each gene is supported by an open reading frame-creating \nmutation that occurred within the primate lineage, and which is not polymorphic \nin any species. Similarly to previous studies we find that the de novo genes \nidentified are short and frequently located near pre-existing genes. Also, they \nmay be associated with Alu elements and prior transcription and RNA-splicing at \nthe locus. Additionally, we report the first case of apparent independent \nlineage sorting of a de novo gene. The gene is present in human and gorilla, \nwhereas chimpanzee has the ancestral noncoding sequence. This indicates a long \nperiod of polymorphism prior to fixation and thus supports a model where de novo \ngenes may, at least initially, have a neutral effect on fitness.",
"New genes can arise through duplication of a pre-existing gene or de novo from \nnon-coding DNA, providing raw material for evolution of new functions in \nresponse to a changing environment. A prime example is the independent evolution \nof antifreeze glycoprotein genes (afgps) in the Arctic codfishes and Antarctic \nnotothenioids to prevent freezing. However, the highly repetitive nature of \nthese genes complicates studies of their organization. In notothenioids, afgps \nevolved from an extant gene, yet the evolutionary origin of afgps in codfishes \nis unknown. Here, we demonstrate that afgps in codfishes have evolved de novo \nfrom non-coding DNA 13-18 Ma, coinciding with the cooling of the Northern \nHemisphere. Using whole-genome sequence data from several codfishes and \nnotothenioids, we find higher copy number of afgp in species exposed to more \nsevere freezing suggesting a gene dosage effect. Notably, antifreeze function is \nlost in one lineage of codfishes analogous to the afgp losses in non-Antarctic \nnotothenioids. This indicates that selection can eliminate the antifreeze \nfunction when freezing is no longer imminent. In addition, we show that \nevolution of afgp-assisting antifreeze potentiating protein genes (afpps) in \nnotothenioids coincides with origin and lineage-specific losses of afgp. The \norigin of afgps in codfishes is one of the first examples of an essential gene \nborn from non-coding DNA in a non-model species. Our study underlines the power \nof comparative genomics to uncover past molecular signatures of genome \nevolution, and further highlights the impact of de novo gene origin in response \nto a changing selection regime."
] | nan |
5a8056a2faa1ab7d2e00001f | [
27484196
] | train | Which web resource for LIR motif-containing proteins in eukaryotes has been developed? | factoid | In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, the iLIR database ( https://ilir.warwick.ac.uk ) has been developed as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. | The iLIR database | [
"Atg8-family proteins are the best-studied proteins of the core autophagic \nmachinery. They are essential for the elongation and closure of the phagophore \ninto a proper autophagosome. Moreover, Atg8-family proteins are associated with \nthe phagophore from the initiation of the autophagic process to, or just prior \nto, the fusion between autophagosomes with lysosomes. In addition to their \nimplication in autophagosome biogenesis, they are crucial for selective \nautophagy through their ability to interact with selective autophagy receptor \nproteins necessary for the specific targeting of substrates for autophagic \ndegradation. In the past few years it has been revealed that Atg8-interacting \nproteins include not only receptors but also components of the core autophagic \nmachinery, proteins associated with vesicles and their transport, and specific \nproteins that are selectively degraded by autophagy. Atg8-interacting proteins \ncontain a short linear LC3-interacting region/LC3 recognition \nsequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for \ntheir interaction with Atg8-family proteins. These proteins are referred to as \nLIR-containing proteins (LIRCPs). So far, many experimental efforts have been \ncarried out to identify new LIRCPs, leading to the characterization of some of \nthem in the past 10 years. Given the need for the identification of LIRCPs in \nvarious organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) \nas a freely available web resource, listing all the putative canonical LIRCPs \nidentified in silico in the proteomes of 8 model organisms using the iLIR \nserver, combined with a Gene Ontology (GO) term analysis. Additionally, a \ncurated text-mining analysis of the literature permitted us to identify novel \nputative LICRPs in mammals that have not previously been associated with \nautophagy."
] | nan |
5c6d6b377c78d69471000039 | [
29095980,
17488757
] | train | Which web-based pedigree editors are available? | list | Pedigreejs and Madeline 2.0 Pedigree Drawing Engine (PDE) | ['Pedigreejs', 'Madeline 2.0 Pedigree Drawing Engine (PDE)'] | [
"MOTIVATION: The collection, management and visualization of clinical pedigree \n(family history) data is a core activity in clinical genetics centres. However, \nclinical pedigree datasets can be difficult to manage, as they are time \nconsuming to capture, and can be difficult to build, manipulate and visualize \ngraphically. Several standalone graphical pedigree editors and drawing \napplications exist but there are no freely available lightweight graphical \npedigree editors that can be easily configured and incorporated into web \napplications.\nRESULTS: We developed 'pedigreejs', an interactive graphical pedigree editor \nwritten in JavaScript, which uses standard pedigree nomenclature. Pedigreejs \nprovides an easily configurable, extensible and lightweight pedigree editor. It \nmakes use of an open-source Javascript library to define a hierarchical layout \nand to produce images in scalable vector graphics (SVG) format that can be \nviewed and edited in web browsers.\nAVAILABILITY AND IMPLEMENTATION: The software is freely available under GPL \nlicence (https://ccge-boadicea.github.io/pedigreejs/).\nCONTACT: tjc29@cam.ac.uk.\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline.",
"The Madeline 2.0 Pedigree Drawing Engine (PDE) is a pedigree drawing program for \nuse in linkage and family-based association studies. The program is designed to \nhandle large and complex pedigrees with an emphasis on readability and \naesthetics. For complex pedigrees, we use a hybrid algorithm in which \nconsanguinous loops are drawn as cyclic graphs whenever possible, but we resort \nto acyclic graphs when matings can no longer be connected without line \ncrossings. A similar hybrid approach is used to avoid line crossings for matings \nbetween distant descendants of different founding groups. Written in \nobject-oriented C++ and released under the GNU General Public License (GPL), \nMadeline 2.0 PDE reads input files specified on the command line and generates \npedigree drawings without user interaction. Pedigree output in scalable vector \ngraphics (SVG) format can be viewed in browsers with native SVG rendering \nsupport or in vector graphics editors. We provide an easy-to-use public web \nservice, which is experimental and still under development.\nAVAILABILITY: http://kellogg.umich.edu/madeline."
] | nan |
5a6e24a5b750ff445500003c | [
29043067
] | train | Which workflow in Bioconductor has been developed for accessing human RNA-seq samples? | factoid | The recount2 resource is composed of over 70,000 uniformly processed human RNA-seq samples spanning TCGA and SRA, including GTEx. | 2 | [
"The recount2 resource is composed of over 70,000 uniformly processed human \nRNA-seq samples spanning TCGA and SRA, including GTEx. The processed data can be \naccessed via the recount2 website and the recount Bioconductor package. This \nworkflow explains in detail how to use the recount package and how to integrate \nit with other Bioconductor packages for several analyses that can be carried out \nwith the recount2 resource. In particular, we describe how the coverage count \nmatrices were computed in recount2 as well as different ways of obtaining public \nmetadata, which can facilitate downstream analyses. Step-by-step directions show \nhow to do a gene-level differential expression analysis, visualize base-level \ngenome coverage data, and perform an analyses at multiple feature levels. This \nworkflow thus provides further information to understand the data in recount2 \nand a compendium of R code to use the data."
] | nan |
5fe31301a43ad31278000039 | [
12719426,
25300489,
10749931,
16100111,
10811823,
26904946,
12783798,
10485849,
11846874
] | train | Which yeast genes encode for condensin? | factoid | Smc2-Smc4 forms the core of the Saccharomyces cerevisiae condensin, which promotes metaphase chromosome compaction . Both SMC2 and SMC4 are essential for chromosome transmission in anaphase . Smc 2-8 suppresses catenanes accumulation, mitotic arrest and growth defects induced by histone depletion at semi-permissive temperature . | 2 | [
"To better understand the contributions that the structural maintenance of \nchromosome proteins (SMCs) make to condensin activity, we have tested a number \nof biochemical, biophysical, and DNA-associated attributes of the Smc2p-Smc4p \npair from budding yeast. Smc2p and Smc4p form a stable heterodimer, the \"Smc2/4 \ncomplex,\" which upon analysis by sedimentation equilibrium appears to reversibly \nself-associate to form heterotetramers. Individually, neither Smc2p nor Smc4p \nhydrolyzes ATP; however, ATPase activity is recovered by equal molar mixing of \nboth purified proteins. Hydrolysis activity is unaffected by the presence of \nDNA. Smc2/4 binds both linearized and circular plasmids, and the binding appears \nto be independent of adenylate nucleotide. High mole ratios of Smc2/4 to plasmid \npromote a geometric change in circular DNA that can be trapped as knots by type \nII topoisomerases but not as supercoils by a type I topoisomerase. Binding \ntitration analyses reveal that two Smc2/4-DNA-bound states exist, one disrupted \nby and one resistant to salt challenge. Competition-displacement experiments \nshow that Smc2/4-DNA-bound species formed at even high protein to DNA mole \nratios remain reversible. Surprisingly, only linear and supercoiled DNA, not \nnicked-circular DNA, can completely displace Smc2/4 prebound to a labeled, \nnicked-circular DNA. To explain this geometry-dependent competition, we present \ntwo models of DNA binding by SMCs in which two DNA duplexes are captured within \nthe inter-coil space of an Smc2/4 heterodimer. Based on these models, we propose \na DNA displacement mechanism to explain how differences in geometry could affect \nthe competitive potential of DNA.",
"The structural organization of chromosomes is essential for their correct \nfunction and dynamics during the cell cycle. The assembly of DNA into chromatin \nprovides the substrate for topoisomerases and condensins, which introduce the \ndifferent levels of superhelical torsion required for DNA metabolism. In \nparticular, Top2 and condensin are directly involved in both the resolution of \nprecatenanes that form during replication and the formation of the \nintramolecular loop that detects tension at the centromeric chromatin during \nchromosome biorientation. Here we show that histone depletion activates the \nspindle assembly checkpoint (SAC) and impairs sister chromatid decatenation, \nleading to chromosome mis-segregation and lethality in the absence of the SAC. \nWe demonstrate that histone depletion impairs chromosome biorientation and \nactivates the Aurora-dependent pathway, which detects tension problems at the \nkinetochore. Interestingly, SAC activation is suppressed by the absence of Top2 \nand Smc2, an essential component of condensin. Indeed, smc2-8 suppresses \ncatenanes accumulation, mitotic arrest and growth defects induced by histone \ndepletion at semi-permissive temperature. Remarkably, SAC activation by histone \ndepletion is associated with condensin-mediated alterations of the centromeric \nchromatin. Therefore, our results reveal the importance of a precise interplay \nbetween histone supply and condensin/Top2 for pericentric chromatin structure, \nprecatenanes resolution and centromere biorientation.",
"This work describes BRN1, the budding yeast homologue of Drosophila Barren and \nXenopus condensin subunit XCAP-H. The Drosophila protein is required for proper \nchromosome segregation in mitosis, and Xenopus protein functions in mitotic \nchromosome condensation. Mutant brn1 cells show a defect in mitotic chromosome \ncondensation and sister chromatid separation and segregation in anaphase. \nChromatid cohesion before anaphase is properly maintained in the mutants. Some \nbrn1 mutant cells apparently arrest in S-phase, pointing to a possible function \nfor Brn1p at this stage of the cell cycle. Brn1p is a nuclear protein with a \nnonuniform distribution pattern, and its level is up-regulated at mitosis. \nTemperature-sensitive mutations of BRN1 can be suppressed by overexpression of a \nnovel gene YCG1, which is homologous to another Xenopus condensin subunit, \nXCAP-G. Overexpression of SMC2, a gene necessary for chromosome condensation, \nand a homologue of the XCAP-E condensin, does not suppress brn1, pointing to \nfunctional specialization of components of the condensin complex.",
"Smc2/4 forms the core of the Saccharomyces cerevisiae condensin, which promotes \nmetaphase chromosome compaction. To understand how condensin manipulates DNA, we \nused two in vitro assays to study the role of SMC (structural maintenance of \nchromosome) proteins and ATP in reconfiguring the path of DNA. The first assay \nevaluated the topology of knots formed in the presence of topoisomerase II. \nUnexpectedly, both wild-type Smc2/4 and an ATPase mutant promoted (+) chiral \nknotting of nicked plasmids, revealing that ATP hydrolysis and the non-SMC \ncondensins are not required to compact DNA chirally. The second assay measured \nSmc2/4-dependent changes in linking number (Lk). Smc2/4 did not induce (+) \nsupercoiling, but instead induced broadening of topoisomer distributions in a \ncooperative manner without altering Lk(0). To explain chiral knotting in \nsubstrates devoid of chiral supercoiling, we propose that Smc2/4 directs chiral \nDNA compaction by constraining the duplex to retrace its own path. In this \nhighly cooperative process, both (+) and (-) loops are sequestered (about one \nper kb), leaving net writhe and twist unchanged while broadening Lk. We have \ndeveloped a quantitative theory to account for these results. Additionally, we \nhave shown at higher molar stoichiometries that Smc2/4 prevents relaxation by \ntopoisomerase I and nick closure by DNA ligase, indicating that Smc2/4 can \nsaturate DNA. By electron microscopy of Smc2/4-DNA complexes, we observed \nprimarily two protein-laden bound species: long flexible filaments and uniform \nrings or \"doughnuts.\" Close packing of Smc2/4 on DNA explains the substrate \nprotection we observed. Our results support the hypothesis that SMC proteins \nbind multiple DNA duplexes.",
"We have characterized five genes encoding condensin components in Saccharomyces \ncerevisiae. All genes are essential for cell viability and encode proteins that \nform a complex in vivo. We characterized new mutant alleles of the genes \nencoding the core subunits of this complex, smc2-8 and smc4-1. Both SMC2 and \nSMC4 are essential for chromosome transmission in anaphase. Mutations in these \ngenes cause defects in establishing condensation of unique (chromosome VIII arm) \nand repetitive (rDNA) regions of the genome but do not impair sister chromatid \ncohesion. In vivo localization of Smc4p fused to green fluorescent protein \nshowed that, unexpectedly, in S. cerevisiae the condensin complex concentrates \nin the rDNA region at the G2/M phase of the cell cycle. rDNA segregation in \nmitosis is delayed and/or stalled in smc2 and smc4 mutants, compared with \nseparation of pericentromeric and distal arm regions. Mitotic transmission of \nchromosome III carrying the rDNA translocation is impaired in smc2 and smc4 \nmutants. Thus, the condensin complex in S. cerevisiae has a specialized function \nin mitotic segregation of the rDNA locus. Chromatin immunoprecipitation (ChIP) \nanalysis revealed that condensin is physically associated with rDNA in vivo. \nThus, the rDNA array is the first identified set of DNA sequences specifically \nbound by condensin in vivo. The biological role of higher-order chromosome \nstructure in S. cerevisiae is discussed.",
"Structural maintenance of chromosomes (SMC) protein complexes, including cohesin \nand condensin, play key roles in the regulation of higher-order chromosome \norganization. Even though SMC proteins are thought to mechanistically determine \nthe function of the complexes, their native conformations and dynamics have \nremained unclear. Here, we probe the topology of Smc2-Smc4 dimers of the S. \ncerevisiae condensin complex with high-speed atomic force microscopy (AFM) in \nliquid. We show that the Smc2-Smc4 coiled coils are highly flexible polymers \nwith a persistence length of only ∼ 4 nm. Moreover, we demonstrate that the SMC \ndimers can adopt various architectures that interconvert dynamically over time, \nand we find that the SMC head domains engage not only with each other, but also \nwith the hinge domain situated at the other end of the ∼ 45-nm-long coiled coil. \nOur findings reveal structural properties that provide insights into the \nmolecular mechanics of condensin complexes.",
"Proper chromatin condensation and sister chromatid resolution are essential for \nthe maintenance of chromosomal integrity during cell division, and is in part \nmediated by a conserved multisubunit apparatus termed the condensin complex. The \ncore subunits of the complex are members of the SMC2 (Structural Maintenance of \nChromosomes) and SMC4 gene families. We have cloned an Arabidopsis gene, \nAtCAP-E1, which is a functional ortholog of the yeast SMC2 gene. A second, \nhighly homologous SMC2 gene, AtCAPE-2, was identified by the Arabidopsis genome \nproject. SMC2 gene expression in Arabidopsis was correlated with the mitotic \nactivity of tissues, with high level expression observed in meristematic cells. \nThe two genes are differentially expressed with AtCAP-E1 accounting for more \nthan 85% of the total SMC2 transcript pool. The titan3 mutant is the result of a \nT-DNA insertion into AtCAP-E1, but other than subtle endosperm defects, titan3 \nis viable and fecund. We identified a T-DNA insertion mutant of AtCAP-E2, which \nshowed no obvious mutant phenotype, indicating that the two genes are \nfunctionally redundant. Genetic crosses were employed to examine the \nconsequences of reduced SMC2 levels. Both male and female gametogenesis were \ncompromised in double mutant spores. Embryo lethality was observed for both \ndouble homozygous and AtCAP-E1(-/-), AtCAP-E2(+/-) plants; arrest occurred at or \nbefore the globular stage and was associated with altered planes of cell \ndivision in both the suspensor and the embryo. Down regulation of both genes by \nantisense technology, as well as in AtCAP-E1(+/-), AtCAP-E2(-/-) plants results \nin meristem disorganization and fasciation. Our data are consistent with the \ninterpretation that threshold levels of SMC2 proteins are required for normal \ndevelopment and that AtCAP-E2 may have a higher affinity for its target than \nAtCAP-E1.",
"The condensin complex in frog extracts, containing two SMC (structural \nmaintenance of chromosomes) and three non-SMC subunits, promotes mitotic \nchromosome condensation, and its supercoiling activity increases during mitosis \nby Cdc2 phosphorylation. Here, we report that fission yeast has the same \nfive-member condensin complex, each of which is essential for mitotic \ncondensation. The condensin complex was purified and the subunits were \nidentified by microsequencing. Cnd1, Cnd2, and Cnd3, three non-SMC subunits \nshowing a high degree of sequence conservation to frog subunits, are essential \nfor viability, and their gene disruption leads to a phenotype indistinguishable \nfrom that observed in cut3-477 and cut14-208, known mutations in SMC4 and \nSMC2-like subunits. Condensin subunits tagged with GFP were observed to alter \ndramatically their localization during the cell cycle, enriched in the nucleus \nduring mitosis, but cytoplasmic during other stages. This stage-specific \nalteration in localization requires mitosis-specific phosphorylation of the T19 \nCdc2 site in Cut3. The T19 site is phosphorylated in vitro by Cdc2 kinase and \nshows the maximal phosphorylation in metaphase in vivo. Its alanine substitution \nmutant fails to suppress the temperature-sensitive phenotype of cut3-477, and \nshows deficiency in condensation, probably because Cut3 T19A remains \ncytoplasmic. Therefore, direct Cdc2 phosphorylation of fission yeast condensin \nmay facilitate its nuclear accumulation during mitosis.",
"The titan (ttn) mutants of Arabidopsis exhibit striking alterations in \nchromosome dynamics and cell division during seed development. Endosperm defects \ninclude aberrant mitoses and giant polyploid nuclei. Mutant embryos differ in \ncell size, morphology and viability, depending on the locus involved. Here we \ndemonstrate that three TTN genes encode chromosome scaffold proteins of the \ncondensin (SMC2) and cohesin (SMC1 and SMC3) classes. These proteins have been \nstudied extensively in yeast and animal systems, where they modulate chromosome \ncondensation, chromatid separation, and dosage compensation. Arabidopsis \ncontains single copies of SMC1 and SMC3 cohesins. We used forward genetics to \nidentify duplicate T-DNA insertions in each gene. These mutants (ttn7 and ttn8) \nhave similar titan phenotypes: giant endosperm nuclei and arrested embryos with \na few small cells. A single SMC2 knockout (ttn3) was identified and confirmed by \nmolecular complementation. The weak embryo phenotype observed in this mutant may \nresult from expression of a related gene (AtSMC2) with overlapping functions. \nFurther analysis of titan mutants and the SMC gene family in Arabidopsis should \nprovide clues to chromosome mechanics in plants and insights into the regulation \nof nuclear activity during endosperm development."
] | nan |
601f19d11cb411341a000073 | [
33037027,
33300275,
33201862,
33287895
] | train | Who received the Nobel prize for development of CRISPR? | list | The 2020 Nobel Prize in Chemistry was awarded to CRISPR-Cas pioneers Emmanuelle Charpentier and Jennifer Doudna. Charpentier and Doudna pioneered the site-specific CRISPR gene-editing technology that has revolutionized cancer research and treatment. | ['Emmanuelle Charpentier', 'Jennifer Doudna,'] | [
"Emmanuelle Charpentier, PhD, and Jennifer Doudna, PhD, who pioneered the \nsite-specific CRISPR gene-editing technology that has revolutionized cancer \nresearch and treatment, were awarded the 2020 Nobel Prize in Chemistry. Many \nCRISPR-based therapies are already in human testing, with gene-edited T cells \nfor blood cancers and solid tumors leading the way.",
"CRISPR (clustered regularly interspaced short palindromic repeats) is a \nprokaryotic immune surveillance system that is used by bacteria to recognize \ngenetic material of infectious organisms, such as phage viruses. Using \nCRISPR-associated (Cas) proteins, this system cleaves foreign nucleic acid into \nfragments, thus defending the bacterium against the attacker. The 2020 Nobel \nPrize in Chemistry was awarded to CRISPR-Cas pioneers Emmanuelle Charpentier and \nJennifer Doudna, who developed the CRISPR-Cas system to precisely edit genomic \nDNA. This technology has exploded at a breathtaking pace and is now used by \nalmost every molecular biology laboratory around the world in a myriad of \norganisms. In this Virtual Issue, the FEBS Journal features articles reviewing \nthe development of CRISPR/Cas9 technology and its applications to understand the \nfunctions of proteins in vivo.",
"Conflict of interest statement: Conflict of interest: JB has served on advisory \nboards for GenSight Biologics; SparingVision; Akouos, Inc; Life Biosciences; and \nOdylia Therapeutics and has consulted for Spark Therapeutics. She served as the \nscientific director for clinical trials run by Spark Therapeutics.",
"In October 2020, Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna won the \nNobel Prize in Chemistry for their pioneering work in precise genome editing \nusing the CRISPR technology. Although CRISPR technology has developed rapidly in \nthe last decade, there are still many uncertainties before eventual use in \nclinical settings. In this mini review, we summarize the current efforts in \naddressing the limitations of CRISPR technology and future directions."
] | nan |
52fa74252059c6d71c00005b | [
21562592,
21475904,
19352322,
19536296,
12200360,
21247248,
15638709,
19746166,
24312663,
24098520,
14683449,
23786330,
9368350,
21205311
] | train | Why are insulators necessary in gene therapy vectors? | summary | a) They inhibit oncogene activation upon vector integration and b) They maximize the probability of vector expression upon integration in heterochromatinic regions | a) They inhibit oncogene activation upon vector integration and b) They maximize the probability of vector expression upon integration in heterochromatinic regions | [
"Gene transfer-based therapeutic approaches have greatly benefited from the \nability of some viral vectors to efficiently integrate within the cell genome \nand ensure persistent transmission of newly acquired transgenes to the target \ncell progeny. However, integration of provirus has been associated with \nepigenetic repercussions that may influence the expression of both the transgene \nand cellular genes close to vector integration loci. The exploitation of genetic \ninsulator elements may overcome both issues through their ability to act as \nbarriers that limit transgene silencing and/or as enhancer-blockers preventing \nthe activation of endogenous genes by the vector enhancer. We established \nquantitative plasmid-based assay systems to screen enhancer-blocker and barrier \ngenetic elements. Short synthetic insulators that bind to nuclear factor-I \nprotein family transcription factors were identified to exert both \nenhancer-blocker and barrier functions, and were compared to binding sites for \nthe insulator protein CTCF (CCCTC-binding factor). Gamma-retroviral vectors \nenclosing these insulator elements were produced at titers similar to their \nnon-insulated counterparts and proved to be less genotoxic in an in vitro \nimmortalization assay, yielding lower activation of Evi1 oncogene expression and \nreduced clonal expansion of bone marrow cells.",
"Regulated expression of a gene of interest is crucial for transgenic research, \nas well as for safe and efficacious gene therapy. The most commonly used \nconditional expression system requires the generation of two transgenic strains, \none carrying an inducible promoter and the other a transactivator. The \ngeneration of conditional transgenic models using this method is costly and time \nconsuming. In this study, we report the design and construction of novel \nsimplified gene delivery vectors that integrate both the regulatory and \nresponsive elements in a single vector. The Tet-On system was used and \nintegrated the inducible promoter and transactivator in a single plasmid, \nbetween which a copy of an insulator was inserted to minimize interference \nbetween the two units. Another copy of an insulator was inserted upstream of the \ntransgene cassette to eliminate transgene silencing and to lower basal \nexpression. The two insulators were in the same orientation. To further decrease \nbasal expression, the most powerful repressor domain containing a \n'kruppel-associated box' of the zinc finger protein NK10 was used and fused to \nTetR in one of the two vectors. The function of this system was confirmed after \nin?vitro transient transfection. The two conditional plasmids were successfully \nconstructed, and the expression of the gene of interest was regulated tightly in \nvitro. In conclusion, the vectors described here may be useful for gene therapy \napplications, as well as for the establishment of conditional animal models.",
"Silencing and position-effect (PE) variegation (PEV), which is due to \nintegration of viral vectors in heterochromatin regions, are considered \nsignificant obstacles to obtaining a consistent level of transgene expression in \ngene therapy. The inclusion of chromatin insulators into vectors has been \nproposed to counteract this position-dependent variegation of transgene \nexpression. Here, we show that the sea urchin chromatin insulator, sns5, \nprotects a recombinant gamma-retroviral vector from the negative influence of \nchromatin in erythroid milieu. This element increases the probability of vector \nexpression at different chromosomal integration sites, which reduces both \nsilencing and PEV. By chromatin immunoprecipitation (ChIP) analysis, we \ndemonstrated the specific binding of GATA1 and OCT1 transcription factors and \nthe enrichment of hyperacetylated nucleosomes to sns5 sequences. The results \nsuggest that this new insulator is able to maintain a euchromatin state inside \nthe provirus locus with mechanisms that are common to other characterized \ninsulators. On the basis of its ability to function as barrier element in \nerythroid milieu and to bind the erythroid specific factor GATA1, the inclusion \nof sns5 insulator in viral vectors may be of practical benefit in gene transfer \napplications and, in particular, for gene therapy of erythroid disorders.",
"Insertional mutagenesis has emerged as a major obstacle for gene therapy based \non vectors that integrate randomly in the genome. Reducing the genotoxicity of \ngenomic viral integration can, in first approximation, be equated with reducing \nthe risk of oncogene activation, at least in the case of therapeutic payloads \nthat have no known oncogenic potential, such as the globin genes. An attractive \nsolution to the problem of oncogene activation is the inclusion of \ninsulators/enhancer-blockers in the viral vectors. In this study we have used \nRecombinase-Mediated Cassette Exchange to characterize the effect of integration \nof globin therapeutic cassettes in the presence or absence of the chicken HS4 \nand three other putative insulators inserted near Stil, Tal1 and MAP17, three \nwell-known cellular proto-oncogenes in the SCL/Tal1 locus. We show that \ninsertion of a Locus Control Region-driven globin therapeutic globin transgene \nhad a dramatic activating effect on Tal1 and Map17, the two closest genes, a \nminor effect on Stil, and no effect on Cyp4x1, a non-expressed gene. Of the four \nelement tested, cHS4 was the only one that was able to suppress this \ntransgene-mediated insertional transcriptional activation. cHS4 had a strong \nsuppressive effect on the activation expression of Map17 but has little or no \neffect on expression of Tal1. The suppressive activity of cHS4 is therefore \npromoter specific. Importantly, the observed suppressive effect of cHS4 on Map17 \nactivation did not depend on its intercalation between the LCR and the Map 17 \npromoter. Rather, presence of one or two copies of cHS4 anywhere within the \ntransgene was sufficient to almost completely block the activation of Map17. \nTherefore, at this complex locus, suppression of transgene-mediated insertional \ntranscriptional activation by cHS4 could not be adequately explained by models \nthat predict that cHS4 can only suppress expression through an enhancer-blocking \nactivity that requires intercalation between an enhancer and a promoter. This \nhas important implications for our theoretical understanding of the possible \neffects of the insertion of cHS4 on gene therapy vectors. We also show that cHS4 \ndecreased the level of expression of the globin transgene. Therefore, the \nbenefits of partially preventing insertional gene activation are in part negated \nby the lower expression level of the transgene. A cost/benefit analysis of the \nutility of incorporation of insulators in gene therapy vectors will require \nfurther studies in which the effects of insulators on both the therapeutic gene \nand the flanking genes are determined at a large number of integration sites. \nIdentification of insulators with minimal promoter specificity would also be of \ngreat value.",
"We have previously described the development of oncoretrovirus vectors for human \ngamma-globin using a truncated beta-globin promoter, modified gamma-globin \ncassette, and alpha-globin enhancer. However, one of these vectors is \ngenetically unstable, and both vectors exhibit variable expression patterns in \ncultured cells, common characteristics of oncoretrovirus vectors for globin \ngenes. To address these problems, we identified and removed the vector sequences \nresponsible for genetic instability and flanked the resultant vector with the \nchicken beta-globin HS4 chromatin insulator to protect expression from \nchromosomal position effects. After determining that flanking with the cHS4 \nelement allowed higher, more uniform levels of gamma-globin expression in MEL \ncell lines, we tested these vectors using a mouse bone marrow transduction and \ntransplantation model. When present, the gamma-globin cassettes from the \nuninsulated vectors were expressed in only 2% to 5% of red blood cells (RBCs) \nlong term, indicating they are highly sensitive to epigenetic silencing. In \ncontrast, when present the gamma-globin cassette from the insulated vector was \nexpressed in 49% +/- 20% of RBCs long term. RNase protection analysis indicated \nthat the insulated gamma-globin cassette was expressed at 23% +/- 16% per copy \nof mouse alpha-globin in transduced RBCs. These results demonstrate that \nflanking a globin vector with the cHS4 insulator increases the likelihood of \nexpression nearly 10-fold, which in turn allows for gamma-globin expression \napproaching the therapeutic range for sickle cell anemia and beta thalassemia.",
"The therapeutic application of recombinant retroviruses and other integrating \ngene transfer vectors has been limited by problems of vector expression and \nvector-mediated genotoxicity. These problems arise in large part from the \ninteractions between vector sequences and the genomic environment surrounding \nsites of integration. Strides have been made in overcoming both of these \nproblems through the modification of deleterious vector sequences, the inclusion \nof better enhancers and promoters, and the use of alternative virus systems. \nHowever, these modifications often add other restrictions on vector design, \nwhich in turn can further limit therapeutic applications. As an alternative, \nseveral groups have been investigating a class of DNA regulatory elements known \nas chromatin insulators. These elements provide a means of blocking the \ninteraction between an integrating vector and the target cell genome in a manner \nthat is independent of the vector transgene, regulatory elements, or virus of \norigin. This review outlines the background, rationale, and evidence for using \nchromatin insulators to improve the expression and safety of gene transfer \nvectors. Also reviewed are topological factors that constrain the use of \ninsulators in integrating gene transfer vectors, alternative sources of \ninsulators, and the role of chromatin insulators as one of several components \nfor optimal vector design.",
"The recent incidents of leukemia development in X-SCID patients after a \nsuccessful treatment of the disease with retroviral gene therapy raised concerns \nregarding the safety of the use of retroviral vectors in clinical gene therapy. \nIn this review, we have tried to re-evaluate the safety issues related to the \nuse of retroviral vectors in human clinical trials and to suggest possible \nappropriate solutions to the issues. As revealed by the X-SCID incident, \noncogenesis caused by retroviral insertional activation of host genes is one of \nthe most prominent risks. An ultimate solution to this problem will be in \nre-engineering retroviral vectors so that the retroviral insertion takes place \nonly at the desired specific sites of the host cell chromosome. This is, \nhowever, a technically demanding tasks, and it will take years to develop \nretroviral vectors with targeted insertion capability. In the mean time, the use \nof chromatin insulators can reduce chances for retrovirus-mediated oncogenesis \nby inhibiting non-specific activation of nearby cellular proto-oncogenes. \nCo-transduction of a suicidal gene under the control of an inducible promoter \ncould also be one of the important safety features, since destruction of \ntransduced cells can be triggered if abnormal growth is observed. Additionally, \nconditional expression of the transgene only in appropriate target cells via the \ncombination of targeted transduction, cell type-specific expression, and \ntargeted local administration will increase the overall safety of the retroviral \nsystems. Finally, splitting of the viral genome, use of self-inactivating (SIN) \nretroviral vectors, or complete removal of the coding sequences for gag, pol, \nand env genes is desirable to virtually eliminate the possibility of generation \nof replication competent retroviruses (RCR).",
"Chromatin insulators separate active transcriptional domains and block the \nspread of heterochromatin in the genome. Studies on the chicken hypersensitive \nsite-4 (cHS4) element, a prototypic insulator, have identified CTCF and USF-1/2 \nmotifs in the proximal 250 bp of cHS4, termed the \"core\", which provide enhancer \nblocking activity and reduce position effects. However, the core alone does not \ninsulate viral vectors effectively. The full-length cHS4 has excellent \ninsulating properties, but its large size severely compromises vector titers. We \nperformed a structure-function analysis of cHS4 flanking lentivirus-vectors and \nanalyzed transgene expression in the clonal progeny of hematopoietic stem cells \nand epigenetic changes in cHS4 and the transgene promoter. We found that the \ncore only reduced the clonal variegation in expression. Unique insulator \nactivity resided in the distal 400 bp cHS4 sequences, which when combined with \nthe core, restored full insulator activity and open chromatin marks over the \ntransgene promoter and the insulator. These data consolidate the known \ninsulating activity of the canonical 5' core with a novel 3' 400 bp element with \nproperties similar to the core. Together, they have excellent insulating \nproperties and viral titers. Our data have important implications in \nunderstanding the molecular basis of insulator function and design of gene \ntherapy vectors.",
"Integrating and expressing stably a transgene into the cellular genome remain \nmajor challenges for gene-based therapies and for bioproduction purposes. While \ntransposon vectors mediate efficient transgene integration, expression may be \nlimited by epigenetic silencing, and persistent transposase expression may \nmediate multiple transposition cycles. Here, we evaluated the delivery of the \npiggyBac transposase messenger RNA combined with genetically insulated \ntransposons to isolate the transgene from neighboring regulatory elements and \nstabilize expression. A comparison of piggyBac transposase expression from \nmessenger RNA and DNA vectors was carried out in terms of expression levels, \ntransposition efficiency, transgene expression and genotoxic effects, in order \nto calibrate and secure the transposition-based delivery system. Messenger RNA \nreduced the persistence of the transposase to a narrow window, thus decreasing \nside effects such as superfluous genomic DNA cleavage. Both the CTF/NF1 and the \nD4Z4 insulators were found to mediate more efficient expression from a few \ntransposition events. We conclude that the use of engineered piggyBac \ntransposase mRNA and insulated transposons offer promising ways of improving the \nquality of the integration process and sustaining the expression of transposon \nvectors.",
"The chromatin insulator cHS4 can reduce silencing chromosomal position effects \nand genotoxicity associated with integrating viral vectors. However, the fully \nactive version of this element can also reduce vector titers and is only \npartially effective. In order to identify alternatives to cHS4, we developed a \nfunctional lentiviral vector-based reporter screen for enhancer-blocking \ninsulators. Using this system, we screened candidate sequences that were \ninitially identified by chromatin profiling for binding by CTCF and for DNase \nhypersensitivity. All 12 analyzed candidates blocked enhancer-promoter activity. \nThe enhancer-blocking activity of the top two candidates was confirmed in two \ncomplementary plasmid-based assays. Studies in a gammaretroviral reporter vector \nindicated these two candidates have little to no effect on vector titers, and do \nnot diminish vector expression in primary mouse bone marrow cultures. Subsequent \nassessment in a mouse in vivo tumor formation model demonstrated that both \ncandidates reduced the rate of gammaretroviral vector-mediated genotoxicity as \neffectively as the cHS4 insulator. In summary, we have developed a novel \nlentiviral vector-based method of screening candidate elements for insulator \nactivity, and have used this method to identify two new insulator elements \ncapable of improving the safety of retroviral vectors without diminishing vector \ntiters or expression. These findings expand the limited arsenal of insulators \nfunctionally validated to reduce the rate of retroviral vector-mediated \ngenotoxicity.",
"Extensive gene therapy studies in preclinical models and in clinical trials \nunderscore the relative safety of onco-retroviral vectors. Up until recently, no \nadverse effects have been reported in nearly 2000 patients that were enrolled in \ngene therapy clinical trials involving onco-retroviral vectors. However, the \nmain safety concern of using onco-retroviral vectors is related to the risk of \nmalignant transformation following oncogene activation due to random \nonco-retroviral genomic integration. Based on primate studies, there is an \napparent low risk of malignancy that is predominately associated with the \noccurrence of chronic retroviremia resulting from replication-competent \nretroviruses (RCR), particularly in immunosuppressed recipient hosts. However, \nin the latest packaging cell lines and vectors, the risk of RCR-generation has \nbeen drastically reduced, primarily by minimizing the homologous overlap between \nvector and helper sequences. Nevertheless, results from a recent preclinical \nstudy in mice and a clinical trial in patients suffering from SCID-X1 strongly \nsuggest that onco-retroviral vectors devoid of RCR can contribute to \nlymphomagenesis by insertional activation of cellular oncogenes. The risk of \ninadvertent germline transmission of onco-retroviral vectors appears to be low, \nespecially relative to the endogenous rate of germline insertion, which is known \nto occur naturally in the human population via transmission of endogenous \nretro-transposons. The strict dependency of onco-retroviral gene transfer on \ncell division is an important safety advantage that significantly limits the \nrisks of horizontal transmission. Since improved onco-retroviral vectors or \ntransduction protocols may result in an increased number of retroviral \nintegrations per cell, this may concomitantly increase the risk of malignant \ntransformation. The use of suicide genes, self-inactivating vectors and/or \nchromosomal insulators is, therefore, warranted to further enhance the safety \nfeatures of onco-retroviral vectors. Detailed analyses of insertion sites \ncombined with long-term clinical follow-up may contribute to a more accurate \nrisk assessment.",
"Gene therapy for the treatment of Wiskott-Aldrich syndrome (WAS) presents an \nalternative to the current use of allogeneic bone marrow transplantation. We \ndescribe the development of a self-inactivating lentiviral vector containing \nchromatin insulators for treatment of WAS and compare a gammaretroviral (MND), \nhuman cellular (EF1α), and the human WASp gene promoter for expression patterns \nin vivo during murine hematopoiesis using the green fluorescent protein (GFP) \nmarker. Compared with the EF1α and the WASp promoters, expression from the MND \npromoter in mouse transplant recipients was much higher in all lineages \nexamined. Importantly, there was sustained expression in the platelets of \nsecondary recipient animals, necessary to correct the thrombocytopenia defect in \nWAS patients. Analysis of WAS protein expression in transduced human \nEBV-immortalized B-cells and transduced patient peripheral blood mononuclear \ncells also demonstrated stronger expression per copy from the MND promoter \ncompared with the other promoters. In addition, when analyzed in an LM02 \nactivation assay, the addition of an insulator to MND-promoter-containing \nconstructs reduced transactivation of the LM02 gene. We propose a clinical trial \ndesign in which cytokine-mobilized, autologous, transduced CD34(+) cells are \nadministered after myelosuppression.",
"Low efficiency of gene transfer is the main obstacle for a clinically effective \ngene therapy at the level of the pluripotent hematopoietic stem cell. Another \nimportant aspect of stem cell gene therapy, the actual expression of the \ntransduced genes, has only been investigated adequately in very few studies, \nmainly for globin genes. Transcriptional silencing and position effects due to \nnegative effects of surrounding chromatin on the expression of randomly \nintegrated vector sequences may seriously jeopardize the success of current gene \ntherapy strategies, even if transduction efficiency can be significantly \nimproved. We propose the incorporation of chromatin insulators in the design of \ngene therapy vectors to overcome the problem of position effects. Chromatin \ninsulators are protein-binding DNA elements that lack intrinsic \npromoter/enhancer activity but shelter genes from transcriptional influence of \nsurrounding chromatin. The best characterized insulators are from Drosophila. We \nhypothesize that the important cellular function of chromatin organization is \nevolutionarily conserved and that human homologs to Drosophila insulator binding \nproteins such as the suppressor of Hairy-wing exist and can be cloned. Using \nthese putative proteins, it should be possible to identify corresponding minimal \nbinding sites with insulator activity. The design and incorporation of effective \nchromatin insulator sequences in the next generation of gene therapy vectors \nshould lead to improved and more predictable expression of therapeutic \ntransgenes and constitute an important step toward clinically effective gene \ntherapy.",
"BACKGROUND: The efficacy and biosafety of lentiviral gene transfer is influenced \nby the design of the vector. To this end, properties of lentiviral vectors can \nbe modified by using cis-acting elements such as the modification of the U3 \nregion of the LTR, the incorporation of the central flap (cPPT-CTS) element, or \npost-transcriptional regulatory elements such as the woodchuck \npost-transcriptional regulatory element (WPRE). Recently, several studies \nevaluated the influence of the incorporation of insulators into the integrating \nlentiviral vector genome on transgene expression level and position effects.\nMETHODS: In the present study, the influence of the matrix attachment region \n(MAR) of the mouse immunoglobulin-κ (Ig-κ) or the chicken lysozyme (ChL) gene \nwas studied on three types of HIV-1-derived lentiviral vectors: \nself-inactivating (SIN) lentiviral vectors (LV), double-copy lentiviral vectors \n(DC) and non-integrating lentiviral vectors (NILVs) in different cell types: \nHeLa, HEK293T, NIH-3T3, Raji, and T Jurkat cell lines and primary neural \nprogenitors.\nRESULTS AND DISCUSSION: Our results demonstrate that the Ig-κ MAR in the context \nof LV slightly increases transduction efficiency only in Hela, NIH-3T3 and \nJurkat cells. In the context of double-copy lentiviral vectors, the Ig-κ MAR has \nno effect or even negatively influences transduction efficiency. In the same \nway, in the context of non-integrating lentiviral vectors, the Ig-κ MAR has no \neffect or even negatively influences transduction efficiency, except in \ndifferentiated primary neural progenitor cells.The ChL MAR in the context of \nintegrating and non-integrating lentiviral vectors shows no effect or a decrease \nof transgene expression in all tested conditions.\nCONCLUSIONS: This study demonstrates that MAR sequences not necessarily increase \ntransgene expression and that the effect of these sequences is probably context \ndependent and/or vector dependent. Thus, this study highlights the importance to \nconsider a MAR sequence in a given context. Moreover, other recent reports \npointed out the potential effects of random integration of insulators on the \nexpression level of endogenous genes. Taken together, these results show that \nthe use of an insulator in a vector for gene therapy must be well assessed in \nthe particular therapeutic context that it will be used for, and must be \nbalanced with its potential genotoxic effects."
] | ['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0044009', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0044008', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002273', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D038101', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D005796', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0006355', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0043035', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0010629', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D005822', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0016458', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015316', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0010628', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0045893', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0045892', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0010468', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009857', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0010467', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004199', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015513'] |
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] | train | Why can't humans synthesize Neu5Gc (N-Glycolylneuraminic acid)? | summary | N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by animals, but not by humans or birds. Humans lack a functional cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate mammalian signal of self. Losing this sugar changed how humans interact with some of our deadliest pathogens: malaria, influenza, and streptococcus among others. | N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by animals, but not by humans or birds. Humans lack a functional cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate mammalian signal of self. Losing this sugar changed how humans interact with some of our deadliest pathogens: malaria, influenza, and streptococcus among others. | [
"Mammals express the sialic acids N-acetylneuraminic acid (Neu5Ac) and \nN-glycolylneuraminic acid (Neu5Gc) on cell surfaces, where they act as receptors \nfor pathogens, including influenza A virus (IAV). Neu5Gc is synthesized from \nNeu5Ac by the enzyme cytidine monophosphate-N-acetylneuraminic acid hydroxylase \n(CMAH). In humans, this enzyme is inactive and only Neu5Ac is produced. Ferrets \nare susceptible to human-adapted IAV strains and have been the dominant animal \nmodel for IAV studies. Here we show that ferrets, like humans, do not synthesize \nNeu5Gc. Genomic analysis reveals an ancient, nine-exon deletion in the ferret \nCMAH gene that is shared by the Pinnipedia and Musteloidia members of the \nCarnivora. Interactions between two human strains of IAV with the sialyllactose \nreceptor (sialic acid--α2,6Gal) confirm that the type of terminal sialic acid \ncontributes significantly to IAV receptor specificity. Our results indicate that \nexclusive expression of Neu5Ac contributes to the susceptibility of ferrets to \nhuman-adapted IAV strains.",
"N-Glycolylneuraminic acid (Neu5Gc) is a non-human sialic acid, which may play a \nsignificant role in human pathologies, such as cancer and vascular disease. \nFurther studies into the role of Neu5Gc in human disease are hindered by limited \nsources of this carbohydrate. Using a chemo-enzymatic approach, Neu5Gc was \naccessed in six steps from glucose. The synthesis allows access to gram-scale \nquantities quickly and economically and produces Neu5Gc in superior quality to \ncommercial sources. Finally, we demonstrate that the synthesized Neu5Gc can be \nincorporated into the cell glycocalyx of human cells, which do not naturally \nsynthesize this sugar. The synthesis produces Neu5Gc suitable for in vitro or in \nvivo use.",
"Some animal influenza A viruses (IAVs) bind not only to N-acetylneuraminic acid \n(Neu5Ac) but also to N-glycolylneuraminic acid (Neu5Gc), which has been \ndiscussed as a virus receptor. Human cells cannot synthesize Neu5Gc due to \ndysfunction of the CMP-Neu5Ac hydroxylase (CMAH) gene, which converts CMP-Neu5Ac \nto CMP-Neu5Gc. However, exogenous Neu5Gc from Neu5Gc-rich dietary sources is \nable to be metabolically incorporated into surfaces of tissue cells and may be \nrelated to enhancement of the infectivity and severity of IAV. Here, we \ninvestigated the receptor function of Neu5Gc on IAV infection in \nNeu5Gc-expressing cells by transfection of the monkey CMAH gene into human cells \nor by incubation with human cells in the presence of N-glycolylmannosamine. \nExpression of Neu5Gc on human cells clearly suppressed infectivity of IAVs that \npossess Neu5Gc binding ability. Furthermore, there was no difference in \ninfectivity of a transfectant virus that included the wild-type HA gene from \nA/Memphis/1/1971 (H3N2), which shows no Neu5Gc binding, between parent MCF7 \ncells and cells stably expressing the monkey CMAH gene (CMAH-MCF7 cells). On the \nother hand, cell entry of the transfectant virus that included the \nNeu5Gc-binding HA gene with a single mutation to Tyr at position Thr155 was \narrested at the stage of internalization from the plasma membrane of the \nCMAH-MCF7 cells. These results indicate that expression of Neu5Gc on the surface \nof human epithelial cells suppresses infection of IAVs that possess Neu5Gc \nbinding ability. Neu5Gc is suggested to work as a decoy receptor of \nNeu5Gc-binding IAVs but not a functional receptor for IAV infection.\nIMPORTANCE: Influenza A viruses (IAVs) bind to the host cell surfaces through \nsialic acids at the terminal of glycoconjugates. For IAV binding to sialic \nacids, some IAVs bind not only to N-acetylneuraminic acid (Neu5Ac) as a receptor \nbut also to N-glycolylneuraminic acid (Neu5Gc). Neu5Gc has been discussed as a \nreceptor of human and animal IAVs. Our results showed that Neu5Gc expression on \nhuman epithelial cells suppresses infection of IAVs that possess Neu5Gc binding \nability. Neu5Gc is suggested to be a \"decoy receptor\" of Neu5Gc-binding IAVs but \nnot a functional receptor for IAV infection. Human cells cannot synthesize \nNeu5Gc because of dysfunction of the CMP-N-acetylneuraminic acid hydroxylase \ngene but can exogenously and metabolically incorporate Neu5Gc from dietary \nsources. The expression of Neu5Gc on human epithelial cells by taking in \nexogenous Neu5Gc from Neu5Gc-rich dietary sources may be related to restriction \nof the infection of IAVs that have acquired Neu5Gc binding ability.",
"Humans are genetically incapable of producing the mammalian sialic acid \nN-glycolylneuraminic acid (Neu5Gc), due to an inactivating mutation in the \nenzyme synthesizing it. Despite this, human cells and tissues appear capable of \nmetabolically incorporating Neu5Gc from exogenous sources, including dietary red \nmeat and dairy products. All normal humans studied are now shown to have \ncirculating Abs against Neu5Gc, with marked differences in isotype levels. The \nquestion arises whether such Abs can adversely affect Neu5Gc-expressing human \ncells or tissues. In this study, we show that although normal human PBMC do not \nincorporate Neu5Gc during in vitro incubation, activated T cells do. Primary \nhuman leukemia cells and human leukemic cell lines are even more efficient at \nincorporation. Human sera containing naturally high levels of anti-Neu5Gc IgG \nAbs (hereafter abbreviated GcIg) deposited complement on Neu5Gc-expressing \nleukemic cells and activated T cells, but not on normal cells. The binding of \nGcIg resulted in complement-mediated cytotoxicity, which was inhibited by heat \ninactivation. Low anti-Neu5Gc IgG-containing human sera did not mediate any of \nthese effects. Mixed killing assays confirmed the 15-fold selective killing of \nleukemic cells over PBMC by GcIg following Neu5Gc feeding. This approach could \npotentially serve as novel way to target malignant cells for death in vivo using \neither natural Abs or anti-Neu5Gc Abs prepared for this purpose. Further studies \nare needed to determine whether deposition of natural GcIg and complement can \nalso target healthy proliferating immune cells for death in vivo following \nincorporation of dietary Neu5Gc.",
"BACKGROUND: Humans are genetically defective in synthesizing the common \nmammalian sialic acid N-glycolylneuraminic acid (Neu5Gc), but can metabolically \nincorporate it from dietary sources (particularly red meat and milk) into \nglycoproteins and glycolipids of human tumors, fetuses and some normal tissues. \nMetabolic incorporation of Neu5Gc from animal-derived cells and medium \ncomponents also results in variable contamination of molecules and cells \nintended for human therapies. These Neu5Gc-incorporation phenomena are \npractically significant, because normal humans can have high levels of \ncirculating anti-Neu5Gc antibodies. Thus, there is need for the sensitive and \nspecific detection of Neu5Gc in human tissues and biotherapeutic products. \nUnlike monoclonal antibodies that recognize Neu5Gc only in the context of \nunderlying structures, chicken immunoglobulin Y (IgY) polyclonal antibodies can \nrecognize Neu5Gc in broader contexts. However, prior preparations of such \nantibodies (including our own) suffered from some non-specificity, as well as \nsome cross-reactivity with the human sialic acid N-acetylneuraminic acid \n(Neu5Ac).\nMETHODOLOGY/PRINCIPAL FINDINGS: We have developed a novel affinity method \nutilizing sequential columns of immobilized human and chimpanzee serum \nsialoglycoproteins, followed by specific elution from the latter column by free \nNeu5Gc. The resulting mono-specific antibody shows no staining in tissues or \ncells from mice with a human-like defect in Neu5Gc production. It allows \nsensitive and specific detection of Neu5Gc in all underlying glycan structural \ncontexts studied, and is applicable to immunohistochemical, enzyme-linked \nimmunosorbent assay (ELISA), Western blot and flow cytometry analyses. \nNon-immune chicken IgY is used as a reliable negative control. We show that \nthese approaches allow sensitive detection of Neu5Gc in human tissue samples and \nin some biotherapeutic products, and finally show an example of how Neu5Gc might \nbe eliminated from such products, by using a human cell line grown under defined \nconditions.\nCONCLUSIONS: We report a reliable antibody-based method for highly sensitive and \nspecific detection of the non-human sialic acid Neu5Gc in human tissues and \nbiotherapeutic products that has not been previously described.",
"N-glycolylneuraminic acid (Neu5Gc) is an immunogenic sugar of dietary origin \nthat metabolically incorporates into diverse native glycoconjugates in humans. \nAnti-Neu5Gc antibodies are detected in all human sera, though with variable \nlevels and epitope-recognition profiles. These antibodies likely play a role in \nseveral inflammation-mediated pathologies including cardiovascular diseases and \ncancer. In cancer, they have dualistic and opposing roles, either stimulating or \nrepressing disease, as a function of their dose, and some of these antibodies \nserve as carcinoma biomarkers. Thus, anti-Neu5Gc antibodies may signify risk of \ninflammation-mediated diseases, and changes in their levels could potentially be \nused to monitor disease progression and/or response to therapy. Currently, it is \ndifficult to determine levels of anti-Neu5Gc antibodies in individual human \nsamples because these antibodies recognize multiple Neu5Gc-epitopes. Here we \ndescribe a simple and specific method for detection and overall estimation of \nhuman anti-Neu5Gc antibodies. We exploit the difference between two mouse models \nthat differ only by Neu5Gc-presence (wild-type) or Neu5Gc-absence (Cmah(-/-) \nknockout). We characterize mouse serum from both strains by HPLC, lectin and \nmass-spectrometry analysis and show the target Neu5Gc-epitopes. We then use \nCmah(-/-) knockout sera to inhibit all non-Neu5Gc-reactivity followed by binding \nto wild-type sera to detect overall anti-Neu5Gc response in a single assay. We \napplied this methodology to characterize and quantify anti-Neu5Gc IgG and IgA in \nsera of patients with Kawasaki disease (KD) at various stages compared to \ncontrols. KD is an acute childhood febrile disease characterized by inflammation \nof coronary arteries that untreated may lead to coronary artery aneurysms with \nrisk of thrombosis and myocardial infarction. This estimated response is \ncomparable to the average of detailed anti-Neu5Gc IgG profile analyzed by a \nsialoglycan microarray. Both assays revealed an elevated response in acute KD \npatients with normal coronaries compared to patients with aneurysm or dilated \ncoronaries. Implications of these findings are discussed.",
"Human polyclonal IgG antibodies directly against the nonhuman sialic acid \nN-glycolylneuraminic acid (Neu5Gc) are potential biomarkers and mechanistic \ncontributors to cancer and other diseases associated with chronic inflammation. \nUsing a sialoglycan microarray, we screened the binding pattern of such \nantibodies (anti-Neu5Gc IgG) in several samples of clinically approved human \nIVIG (IgG). These results were used to select an appropriate sample for a \nmultistep affinity purification of the xeno-autoantibody fraction. The sample \nwas then analyzed via our multienzyme digestion procedure followed by nano \nliquid chromatography (nanoLC) coupled to linear ion trap-Fourier transform mass \nspectrometry (LTQ-FTMS). We used characteristic and unique peptide sequences to \ndetermine the IgG subclass distribution and thus provided direct evidence that \nall four IgG subclasses can be generated during a xeno-autoantibody immune \nresponse to carbohydrate Neu5Gc-antigens. Furthermore, we obtained a significant \namount of sequence coverage of both the constant and variable regions. The \napproach described here, therefore, provides a way to characterize these \nclinically significant antibodies, helping to understand their origins and \nsignificance.",
"Human sialic acid biology is unusual and thought to be unique among mammals. \nHumans lack a functional cytidine monophosphate-N-acetylneuraminic acid \nhydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate \nmammalian signal of self. Losing this sugar changed how humans interact with \nsome of our deadliest pathogens: malaria, influenza, and streptococcus among \nothers. We show that the New World monkeys, comprising the third of all primate \nspecies, have human-like sialic acid biology. They have lost Neu5Gc because of \nan independent CMAH inactivation ~30 million years ago (mya) (compared to ~3 mya \nin hominids). This parallel loss of Neu5Gc opens sialic acid biology to \ncomparative phylogenetic analysis and reveals an unexpected conservation \npriority. New World monkeys risk infection by human pathogens that can recognize \ncells in the absence of Neu5Gc. This striking molecular convergence provides a \nmechanism that could explain the long-standing observation that New World \nmonkeys are susceptible to some human diseases that cannot be transmitted to \nother primates.",
"AB(5) toxins comprise an A subunit that corrupts essential eukaryotic cell \nfunctions, and pentameric B subunits that direct target-cell uptake after \nbinding surface glycans. Subtilase cytotoxin (SubAB) is an AB(5) toxin secreted \nby Shiga toxigenic Escherichia coli (STEC), which causes serious \ngastrointestinal disease in humans. SubAB causes haemolytic uraemic \nsyndrome-like pathology in mice through SubA-mediated cleavage of BiP/GRP78, an \nessential endoplasmic reticulum chaperone. Here we show that SubB has a strong \npreference for glycans terminating in the sialic acid N-glycolylneuraminic acid \n(Neu5Gc), a monosaccharide not synthesized in humans. Structures of SubB-Neu5Gc \ncomplexes revealed the basis for this specificity, and mutagenesis of key SubB \nresidues abrogated in vitro glycan recognition, cell binding and cytotoxicity. \nSubAB specificity for Neu5Gc was confirmed using mouse tissues with a human-like \ndeficiency of Neu5Gc and human cell lines fed with Neu5Gc. Despite lack of \nNeu5Gc biosynthesis in humans, assimilation of dietary Neu5Gc creates \nhigh-affinity receptors on human gut epithelia and kidney vasculature. This, and \nthe lack of Neu5Gc-containing body fluid competitors in humans, confers \nsusceptibility to the gastrointestinal and systemic toxicities of SubAB. \nIronically, foods rich in Neu5Gc are the most common source of STEC \ncontamination. Thus a bacterial toxin's receptor is generated by metabolic \nincorporation of an exogenous factor derived from food.",
"Human heterophile antibodies that agglutinate animal erythrocytes are known to \ndetect the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc). This \nmonosaccharide cannot by itself fill the binding site (paratope) of an antibody \nand can also be modified and presented in various linkages, on diverse \nunderlying glycans. Thus, we hypothesized that the human anti-Neu5Gc antibody \nresponse is diverse and polyclonal. Here, we use a novel set of natural and \nchemoenzymatically synthesized glycans to show that normal humans have an \nabundant and diverse spectrum of such anti-Neu5Gc antibodies, directed against a \nvariety of Neu5Gc-containing epitopes. High sensitivity and specificity assays \nwere achieved by using N-acetylneuraminic acid (Neu5Ac)-containing probes \n(differing from Neu5Gc by one less oxygen atom) as optimal background controls. \nThe commonest anti-Neu5Gc antibodies are of the IgG class. Moreover, the range \nof reactivity and Ig classes of antibodies vary greatly amongst normal humans, \nwith some individuals having remarkably large amounts, even surpassing levels of \nsome well-known natural blood group and xenoreactive antibodies. We purified \nthese anti-Neu5Gc antibodies from individual human sera using a newly developed \naffinity method and showed that they bind to wild-type but not Neu5Gc-deficient \nmouse tissues. Moreover, they bind back to human carcinomas that have \naccumulated Neu5Gc in vivo. As dietary Neu5Gc is primarily found in red meat and \nmilk products, we suggest that this ongoing antigen-antibody reaction may \ngenerate chronic inflammation, possibly contributing to the high frequency of \ndiet-related carcinomas and other diseases in humans.",
"BACKGROUND: N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by \nanimals, but not by humans or birds. However, it can be incorporated in human \ncells and can trigger immune response. In the present study, we detected \nanti-Neu5Gc antibodies in samples of the general population and of patients \nsuffering from hypothyroidism/Hashimoto's disease, which is known to have \nautoimmune origin.\nMETHODS: Antibodies were measured using enzyme-immunosorbent techniques.\nRESULTS: Serum anti-Neu5Gc IgG antibodies were higher in patients with \nhypothyroidism (mean: 14.8 ± 15.9 μg/mL, median: 10.0 μg/mL, P = 0.0003, \nMann-Whitney) and even higher in the group with Hashimoto's thyroiditis (mean: \n31.1 ± 16.3 μg/mL, median: 27.2 μg/mL, P = 0.0000, Mann-Whitney) compared to the \ngeneral population (mean: 5.3 ± 4.7 μg/mL, median : 4 μg/mL). All anti-TPO \npositive samples had anti-Neu5Gc antibody concentration higher than the mean \nvalue of the general population while anti-TPO concentration was increased as \nanti-Neu5Gc concentration increased. Low concentrations of IgA and IgM \nantibodies were measured in both general population and patient groups.\nCONCLUSION: The increased values of anti-Neu5Gc antibodies in patients with \nhypothyroidism/Hashimoto's disease and the correlation of anti-TPO incidence \nwith increased anti-Neu5Gc concentration raise the possibility of an association \nbetween anti-Neu5Gc antibody development and autoimmune hypothyroidism.",
"A concern recently has been raised that human embryonic stem cell (HESC) lines \ncultured with currently available methods may have limited clinical usefulness \ndue to the immunogenicity of the nonhuman sialic acid Neu5Gc incorporated into \ntheir membranes during culturing. We find this concern has little relevance to \nneural differentiation protocols with B27/N2/noggin because of the gradual \ndecline of Neu5Gc to less than 1% in differentiating cells upon switching to \nB27/N2 medium.",
"The expression of N-glycolylneuraminic acid (Neu5Gc) and the cytotoxic T cell \n(CT) carbohydrate can impact the severity of muscular dystrophy arising from the \nloss of dystrophin in mdx mice. Here, we describe the expression of these two \nglycans in skeletal muscles of dogs and humans with or without \ndystrophin-deficiency. Neu5Gc expression was highly reduced (>95%) in muscle \nfrom normal golden retriever crosses (GR, n = 3) and from golden retriever with \nmuscular dystrophy (GRMD, n = 5) dogs at multiple ages (3, 6 and 13 months) when \ncompared to mouse muscle, however, overall sialic acid expression in GR and GRMD \nmuscles remained high at all ages. Neu5Gc was expressed on only a minority of \nGRMD satellite cells, CD8⁺ T lymphocytes and macrophages. Human muscle from \nnormal (no evident disease, n = 3), Becker (BMD, n = 3) and Duchenne (DMD, \nn = 3) muscular dystrophy individuals had absent to very low Neu5Gc staining, \nbut some punctate intracellular muscle staining was present in BMD and DMD \nmuscles. The CT carbohydrate was localized to the neuromuscular junction in GR \nmuscle, while GRMD muscles had increased expression on a subset of myofibers and \nmacrophages. In humans, the CT carbohydrate was ectopically expressed on the \nsarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. \nThese data are consistent with the notion that altered Neu5Gc and CT \ncarbohydrate expression may modify disease severity resulting from dystrophin \ndeficiency in dogs and humans."
] | nan |
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] | train | Why does cranberry juice help combat urinary tract infections? | summary | Cranberry products affect the surface properties, such as fimbriae and lipopolysaccharides, and adhesion of fimbriated and nonfimbriated E. coli. | Cranberry products affect the surface properties, such as fimbriae and lipopolysaccharides, and adhesion of fimbriated and nonfimbriated E. coli. | [
"Flavonoids, present in high levels in cranberries, are potent bioactives known \nfor their health-promoting benefits, but cranberry beverages (CB) are not \ntypically recommended as part of a healthy diet. We examine the association \nbetween CB consumption with macronutrient intake and weight status. Data for US \nadults (≥19 years, n = 10,891) were taken from the National Health and Nutrition \nExamination Survey (NHANES) Survey 2005-2008. Total CB consumption was measured \nover two non-consecutive 24-h dietary recalls. Linear and logistic regression \nmodels adjusting for important covariates were used to examine predicted \ndifferences between CB consumers and non-consumers on macronutrient and \nanthropometric outcomes. Results are weighted to be nationally representative. \nCB consumers (n = 581) were older (>50 year) non-Hispanic black females. They \nconsumed an average 221 mL (7.5 oz) CB per day. In fully adjusted models CB \nconsumers (vs. non-consumers) had higher carbohydrates and total sugars and \nlower percent energy from protein and total fat (all p < 0.001), but no \ndifference in total energy. A significantly higher proportion of CB consumers \nwere predicted to be normal weight (BMI < 25 kg/m2; p = 0.001) and had to have \nlower waist circumferences (p = 0.001). Although there was not a significant \ntrend across level of CB intake, low and middle level CB consumers compared to \nnon-consumers were more likely to be normal weight (p < 0.001) and less likely \nto be overweight/obese (BMI ≥ 25 kg/m2, p < 0.001). Despite having slightly \nhigher daily macronutrient intakes, CB consumers have more desirable \nanthropometric measures compared to non-consumers.",
"Cranberry juice cocktail (CJC) has been shown to inhibit the formation of \nbiofilm by uropathogenic Escherichia coli. In order to investigate whether the \nanti-adhesive components could reach the urinary tract after oral consumption of \nCJC, a volunteer was given 16 oz of either water or CJC. Urine samples were \ncollected at 0, 2, 4, 6, and 8 hours after consumption of a single dose. The \nability of compounds in the urine to influence bacterial adhesion was tested for \nsix clinical uropathogenic E. coli strains, including four P-fimbriated strains \n(B37, CFT073, BF1023, and J96) and two strains not expressing P-fimbriae but \nexhibiting mannose-resistant hemagglutination (B73 and B78). A non-fimbriated \nstrain, HB101, was used as a control. Atomic force microscopy (AFM) was used to \nmeasure the adhesion force between a silicon nitride probe and bacteria treated \nwith urine samples. Within 2 hours after CJC consumption, bacteria of the \nclinical strains treated with the corresponding urine sample demonstrated lower \nadhesion forces than those treated with urine collected before CJC consumption. \nThe adhesion forces continued decreasing with time after CJC consumption over \nthe 8-hour measurement period. The adhesion forces of bacteria after exposure to \nurine collected following water consumption did not change. HB101 showed low \nadhesion forces following both water and CJC consumption, and these did not \nchange over time. The AFM adhesion force measurements were consistent with the \nresults of a hemagglutination assay, confirming that oral consumption of CJC \ncould act against adhesion of uropathogenic E. coli.",
"Question Plusieurs enfants de ma clinique se rétablissent d’une infection des \nvoies urinaires (IVU). La mère de l’un d’eux m’a demandé si je recommandais le \njus de canneberge pour prévenir de futurs épisodes d’IVU. On lui avait \nrecommandé d’en boire lorsqu’elle a souffert d’une IVU il y a quelques mois. \nRéponse Il a été démontré que le jus de canneberge était efficace pour prévenir \nl’adhésion de bactéries comme l’Escherichia coli à l’épithélium de la vessie. \nLes données scientifiques actuelles appuient l’utilisation du jus de canneberge \npour la prévention des IVU chez les femmes adultes, mais il n’en existe pas pour \nle moment sur la prévention des IVU chez l’enfant. Si le jus de canneberge est \ntrès sécuritaire pour la plupart des enfants, son acidité fait que son goût est \nmoins apprécié des enfants. Il reste aussi à déterminer la quantité de jus de \ncanneberge nécessaire pour prévenir les IVU chez les enfants.",
"Most research suggests that ingestion of cranberry juice may be useful in \npreventing urinary tract infections. This pilot study examines the effect of \ndrinking moderate amounts of commercially available cranberry juice cocktail on \nurinary pH in older, institutionalized adults. The results of the study have \nimplications for home care nurses who have similar patients in their case loads.",
"Previous clinical research has suggested that the consumption of cranberry \nproducts prevents the adhesion of Escherichia coli to uroepithelial cells by \ncausing changes in bacterial fimbriae. Atomic force microscopy was used to probe \nthe adhesion forces between E. coli (nonfimbriated strain HB101 and the \nP-fimbriated variant HB101pDC1) and a model surface (silicon nitride), to \ndetermine the effect of growth in cranberry products on bacterial adhesion. \nBacteria were grown in tryptic soy broth supplemented with either light \ncranberry juice cocktail (L-CJC) or cranberry proanthocyanidins (PACs). Growth \nof E. coli HB101pDC1 and HB101 in L-CJC or PACs resulted in a decrease in \nadhesion forces with increasing number of cultures. In a macroscale \nbacteria-uroepithelial cell adhesion assay a decrease in bacterial attachment \nwas observed for E. coli HB101pDC1 grown in L-CJC or PACs. This effect was \nreversible because bacteria that were regrown in cranberry-free medium regained \ntheir ability to attach to uroepithelial cells, and their adhesion forces \nreverted to the values observed in the control condition. Exposure to increasing \nconcentrations of L-CJC resulted in a decrease of bacterial attachment to \nuroepithelial cells for the P-fimbriated strain after L-CJC treatment (27% by \nweight) and after PACs treatment (345.8 microg/mL). Cranberry products affect \nthe surface properties, such as fimbriae and lipopolysaccharides, and adhesion \nof fimbriated and nonfimbriated E. coli. The concentration of cranberry products \nand the number of cultures the bacteria were exposed to cranberry determines how \nmuch the adhesion forces and attachment are altered.",
"Proanthocyanidin is commonly used for inhibiting urinary tract infection (UTI) \nof sensitive strains of Escherichia coli. The aim of this study was to \ninvestigate the effect of proanthocyanidin on adherence of uropathogenic \nmulti-drug resistant E. coli to uroepithelial cells, which has not yet been \ninvestigated so far. Extracts of the purified proanthocyanidin were prepared \nfrom dried cranberry juice. Purity and structural assignment of proanthocyanidin \nwas assessed using high performance liquid chromatography and (13)C nuclear \nmagnetic resonance spectroscopy, respectively. Subsequently, its affect on \nmulti-drug resistant bacteria as well as quantification of anti-adherence \nbioactivity on human vaginal and bladder epithelial cells was appraised. \nInhibition of adherence to an extent of about 70% with multi-drug resistant E. \ncoli strains was observed on uroepithelial cell. The anti-adherence bioactivity \nof the proanthocyanidin was detected at concentrations of 10-50 µg/ml with \nsignificant bacteriuria. Probable proanthocyanidin through A-type linkages \neither combines to P-fimbriae of bacterial cells or modifies the structural \nentity of P-fimbriae and inhibits bacterial adherence to uroepithelial cells. \nThe proanthocyanidin exhibited anti-adherence property with multi-drug resistant \nstrains of uropathogenic P-fimbriated E. coli with in vitro study. Hence \nproanthocyanidin may be considered as an inhibitory agent for multi-drug \nresistant strains of E. coli adherence to uroepithelial cells.",
"Recurrent urinary tract infections are a frequent problem in urological \npractice. Long-term antibiotic prophylaxis can cause resistance of some \nintestinal bacteria, and after therapy is stopped, infections often resume. In \ncontrolled studies, general recommendations for prophylaxis were shown to \ninhibit reinfection. One of these recommendations is the consumption of \ncranberries. A review of the literature in PubMed as well as the recently \npublished Cochrane database systematic review confirmed that daily consumption \nof cranberries prevents recurrent urinary tract infections. In vitro studies \nhave shown that binding of the P fimbriae of Escherichia coli to the \nuroepithelial tissue can be inhibited in the presence of proanthocyanidins, the \nactive ingredient of cranberries. In clinical studies, the evidence is not so \npronounced. Many other bacteria have fimbriae, but only a few subpopulations \nhave P fimbriae. P fimbriae are frequent in E. coli, so this adhesion can be \nprevented. However, in a subanalysis of randomized and controlled studies, it \nwas shown that women with recurrent urinary tract infections might profit from \nconsuming cranberries.",
"Cranberry (Vaccinium macrocarpon) has been used for decades to prevent urinary \ntract infections (UTIs) that are among the most common bacterial infections in \nwomen. As to the traditional use of cranberry and its A-type proanthocyanidins' \nability to inhibit adherence of the bacterial P fimbriae in a dose-dependent \nmanner, clinical trials have been conducted on different subpopulations. A \nCochrane meta-analysis in 244 females with symptomatic UTI suggests that the \neffect was more pronounced in women with recurrent UTIs than elderly males and \nfemales or people requiring catheterization. A first head-to-head trial in older \nfemales has been published comparing effectiveness of a low-dose antibiotic \nversus cranberry in which investigators suggest that cranberry products may have \na role in older females with recurrent UTI. Still with regard to antibiotic \ntreatment in women, a recently published study investigated also the potential \ncranberry juice interaction with beta-lactam antibiotics supporting the \nhypothesis that cranberry juice in usual quantities as prophylaxis for UTI is \nnot likely to alter the pharmacokinetics of these oral antibiotics. In addition, \nthe effects of cranberry in pregnant female patients have been investigated. A \nfirst pilot trial has been published in which, while a possible protective \neffect was shown, more than one third of the females withdrew mainly for \ngastrointestinal upset.",
"CONTEXT: Cranberry juice has long been recognized in folk medicine as a \ntherapeutic agent, mainly in urinary tract infections. Its proposed mechanism of \naction is antiadhesion of bacteria.\nOBJECTIVE: Investigation of the potential antiadhesion effect of nondialyzed \nmaterial of cranberry (NDM) via its influence on secretion, gene expression, and \npromoter activity of the fructosyltransferase (FTF), which is among the \nextracellular enzymes associated with dental biofilm formation and pathogenesis \nof oral bacteria.\nMAIN OUTCOME MEASURES: Secretion of FTF from Streptococcus mutans, in the \npresence of NDM, was measured by immunoblotting and confocal scanning laser \nmicroscopy. Its influence on ftf gene expression was determined by reverse \ntranscription followed by real-time RT-PCR. The luciferase assay was used to \ndetect bioluminescence expressed by the ftf promoter activity of bacteria \nexposed to NDM.\nRESULTS: NDM at concentrations between 0.2/mL and 1mg/mL significantly (P<.05) \ndecreased secretion of extracellular FTF, as well as down-regulated ftf \nexpression in a dose-dependent manner. NDM also markedly reduced the luciferase \nactivity under the ftf promoter.",
"Basic studies have proven that cranberries may prevent urinary tract infections \nthrough changing the adhesiveness of Escherichia coli (E. coli) to urothelial \ncells. Various cranberry preparations, including extract powder, capsules, and \njuice, have been shown to be effective in clinical and epidemiological research. \nBecause cranberries are most commonly consumed as juice in a diluted \nconcentration, the aim of this study was to investigate whether the equivalent \ndaily dose of cranberry juice is sufficient to modify host urine to change the \nuropathogenicity of E. coli. Urine from rats taking an equivalent daily dose of \ncranberry juice has been shown to decrease the capability of E. coli in \nhemagglutination, urothelium adhesion, nematode killing, and biofilm formation. \nAll these changes occurred after E. coli was incubated in cranberry \nmetabolite-containing urine, defined as urine opsonization. Urine opsonization \nof E. coli resulted in 40.9% (p = 0.0038) decrease in hemagglutination ability, \n66.7% (p = 0.0181) decrease in urothelium adhesiveness, 16.7% (p = 0.0004) \nincrease in the 50% lethal time in killing nematodes, and 53.9% (p = 5.9 × \n10(-4)) decrease in biofilm formation. Thus, an equivalent daily dose of \ncranberry juice should be considered sufficiently potent to demonstrate urine \nopsonization in E. coli.",
"OBJECTIVE: This study compares the effects of daily cranberry juice to those of \nLactobacillus in children with recurrent urinary tract infections (UTIs).\nMATERIAL AND METHODS: Eighty-four girls aged between 3 and 14 years were \nrandomized to cranberry, Lactobacillus or control in three treatment arms: G1, \ncranberry juice 50 ml daily (n=28); G2, 100 ml of Lactobacillus GG drink on 5 \ndays a month (n=27); and G3, controls (n=29). The study lasted for 6 months.\nRESULTS: Only four subjects withdrew: 1/28 (3.5%) from G1, 1/27 (3.7%) from G2 \nand 2/29 (6.8%) from G3, because of poor compliance to the established protocol. \nThere were 34 episodes of UTIs in this cohort: 5/27 (18.5%) in G1, 11/26 (42.3%) \nin G2 and 18/27 (48.1%) in the G3, with at least one episode of infection \n(p<0.05).\nCONCLUSION: These data suggest that daily consumption of concentrated cranberry \njuice can significantly prevent the recurrence of symptomatic UTIs in children."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D029799', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014552', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D014551'] |
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11984063
] | train | Why does the prodrug amifostine (ethyol) create hypoxia? | summary | After the administration of Prodrug amifostine the cells of the tissue prefer anaerobic glycolysis rather than regular cellular aerobic respiration. By the beggining of anaerobic glycolysis the inducible by hypoxia proteins are induced and by all these molecules the hypoxic conditions consist of. | After the administration of Prodrug amifostine the cells of the tissue prefer anaerobic glycolysis rather than regular cellular aerobic respiration. By the beggining of anaerobic glycolysis the inducible by hypoxia proteins are induced and by all these molecules the hypoxic conditions consist of. | [
"BACKGROUND/AIMS: Hepatic and biliary toxicity are still significant problems \nafter intraarterial hepatic chemoembolization for liver metastases from large \nbowel cancers. In about 30-60% of the patients hepatic and biliary toxicity are \nthe limiting aspects of intraarterial hepatic chemoembolization and exclude a \nlot of patients from a repeated beneficial treatment. Amifostine (Ethyol) is a \nprodrug that must be dephosphorylated to the free thiol in which form it can \ndetoxify free oxygen radicals generated by radiation, hypoxia and by drugs such \nanthracyclines, platinum analogues and alkylating agents. Amifostine as inactive \nprodrug is primarily metabolized at the tissue site by membrane alkaline \nphosphatase, which is highly active in the cell membranes of normal endothelial \ncells and biliary tree cells but not in the cell membranes and neovascular \ncapillaries of tumor. When dephosphorylated to WR-1065, amifostine is rapidly \ntaken up into normal liver cells by a carrier-mediated facilitated diffusion \ntransport process. The resulting high thiol content in normal liver tissue \n(biliary cells and hepatocytes) compared with the negligible concentration in \nliver metastases from large bowel cancers probably provides for selective drug \nresistance to intraarterial hepatic chemoembolization protecting normal tissue \nand allowing full therapeutic effect on tumor.\nMETHODOLOGY: From May 1997 we planned a phase I study in patients receiving \nintraarterial hepatic chemoembolization for liver metastases from large bowel \ncancers. We started at 200 mg/m2 dissolved in 250 cc of normal saline given in \n15 min in the intrahepatic artery 20 min before an intraarterial hepatic \nchemoembolization consisting of mitomycin 10 mg/m2, epirubicin-50, cisplatin-60 \ndiluted in 10 mL of contrast media, mixed in 15 mL of lipiodol UF followed by a \ngelfoam powder solution until stagnation of the flow. The escalating dose, every \n3 patients, was: 200 mg/m2, 250 mg/m2, 300 mg/m2, 350 mg/m2.\nRESULTS: Toxicity has been observed at 350 mg/m2: 1 patient reported transient \nhypotension (Blood pressure 70/50 mm Hg), 1 patient had skin flushing and \ndyspnoea. 300 mg/m2 are well tolerated and seem to reduce the level of \ntransaminases, lactic acid dehydrogenase, and gamma-glutamyl transferase. Also \nthe duration of necrotic damage, always observed after intraarterial hepatic \nchemoembolization, seems shorter compared with historical controls.\nCONCLUSIONS: Amifostine can be certainly administered at 300 mg/m2 as \nintraarterial infusion and could be a significant step to ameliorate the \ntherapeutic ratio of intraarterial hepatic chemoembolization.",
"Placental extracts have been reported to have anti-oxidative and \nanti-inflammatory activities. Because there is increasing evidence that ionizing \nradiation induces the release of reactive oxygen species (ROS) and inflammatory \ncytokines, we examined the protective effects of a placental extract against \nradiation injury. C57BL/6 mice were exposed to 1 Gy of γ-ray radiation every day \nfor 5 days, and placental extract (1 mg/day) was administrated orally soon after \neach exposure. At 2 days after the last irradiation, mice were euthanized to \nexamine the numbers, colony-forming capacity, and DNA damage of stem/progenitor \ncells in the peripheral blood and bone marrow. To understand the related \nmechanisms, we also measured the levels of intracellular and mitochondrial ROS, \nand 8-OHdG in the plasma and urine, and IL-6 and TNF-α in the plasma. Compared \nwith the placebo treatment, oral administration of placental extract \nsignificantly increased the number and colony-forming capacity, but decreased \nthe DNA damage of bone marrow stem/progenitor cells. However, neither the levels \nof intracellular and mitochondrial ROS in bone marrow cells, nor the levels of \n8-OHdG in the urine and plasma significantly differed between groups. \nInterestingly, in comparison with the placebo treatment, placental extract \nsignificantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α \nin the plasma. Placental extract significantly attenuated the acute radiation \ninjury to bone marrow-derived stem/progenitor cells, and this protection is \nlikely to be related to the anti-inflammatory activity of the placental extract.",
"Conclusive research has shown that regions of acute/chronic hypoxia, which exist \nwithin the majority of solid tumours, have a profound influence on the \ntherapeutic outcome of cancer chemotherapy and radiotherapy and are a strong \nprognostic factor of disease progression and survival. A strong argument \ntherefore exists for assessing the hypoxic fraction of tumours, prior to patient \ntreatment, and to tailor this treatment accordingly. Tumour hypoxia also \nprovides a powerful physiological stimulus that can be exploited as a \ntumour-specific condition, allowing for the rationale design of \nhypoxia-activated anticancer drugs or novel hypoxia-regulated gene therapy \nstrategies.",
"BACKGROUND: Radioprotective modalities such as dose fractionation and \npharmacologic agents such as amifostine have been used to protect bone and other \ntypes of normal tissue from the damaging effects of ionizing radiation without \nsignificantly impacting tumor kill. To better understand the cellular mechanism \nof radioprotection of osseous tissue, the authors sought to determine the effect \nof dose fractionation and amifostine on isolated osteoblasts.\nMETHODS: Isolated primary rat calvarial osteoblasts were exposed to single or \nfractionated doses of ionizing radiation both with and without amifostine \npretreatment. Endpoints included cell growth (n = 4), vascular endothelial \ngrowth factor production as measured by enzyme-linked immunosorbent assay (n = \n3), and early osteodifferentiation as measured by a quantitative alkaline \nphosphatase assay (n = 3).\nRESULTS: Both dose fractionation and amifostine protect osteoblasts from the \ngrowth inhibitory effects of ionizing radiation. Fractionation but not \namifostine was protective for hypoxia-induced vascular endothelial growth factor \nproduction (used as a surrogate marker of normal osteoblast function). Neither \nfractionation nor amifostine could prevent the inhibitory effect of ionizing \nradiation on normal osteoblast osteodifferentiation as measured by alkaline \nphosphatase production.\nCONCLUSIONS: Both dose fractionation and amifostine have valid roles as \nradioprotectants for osteoblasts and can act in an additive fashion. \nRadioprotection of cell growth and viability does not necessarily correlate with \npreservation of normal cellular function. Combination protocols involving dose \nfractionation and amifostine may be effective in radioprotection of osteoblasts \nand normal osseous tissue.",
"PURPOSE: Tumor hypoxia and low intrinsic radiosensitivity may counteract the \nefficacy of standard radiotherapy for locally advanced head and neck cancer \n(HNC). We investigated the involvement of hypoxia-regulated proteins (Hypoxia \ninducible factors HIF1alpha, HIF2alpha and carbonic anhydrase CA9) in HNC \nresistance to accelerated and hypofractionated radiotherapy.\nMATERIALS AND METHODS: Thirty-nine patients with locally advanced HNC received \n15 daily fractions of 3.4 Gy amounting to a total tumor dose of 51 Gy \n(equivalent to 63 Gy in four weeks--one week split); this was combined with \nplatinum chemotherapy and amifostine cytoprotection administered subcutaneously. \nImmunohistochemical analysis of hypoxia-regulated proteins, namely HIF1alpha, \nHIF2alpha and CA9, was performed in formalin-fixed paraffin-embedded tissues \nobtained prior to radio-chemotherapy.\nRESULTS: HIF1alpha and HIF2alpha were expressed in the nuclei and cytoplasm of \ncancer cells, while CA9 had a membrane reactivity. A high expression of \nHIF1alpha, HIF2alpha and CA9 was noted in 21/39 (53.8%), 20/39 (51.3%) and 23/39 \n(58.9%) cases, respectively. Complete response was obtained in 85.2% of patients \nand HIF1alpha was marginally related with persistent disease after RT (p = \n0.05). HIF1alpha was significantly associated with poor local relapse free \nsurvival (LRFS) (p = 0.006) and overall survival (p = 0.008), whilst HIF2alpha \nwas not. A significant association of CA9 expression with poor LRFS was noted (p \n= 0.01).\nCONCLUSION: In accord with previously reported studies, high levels of the \nhypoxia regulated proteins HIF1alpha and CA9 in HNC predict resistance to \nplatinum based radio-chemotherapy. Whether HIF2alpha expressing tumors are more \nsensitive to larger radiotherapy fractions, compared to standard radiotherapy \nfractionation, is an issue that deserves further investigation.",
"After several decades of preclinical and clinical research, the first approved \nradioprotective drug, amifostine, is being used in clinical practice. Amifostine \nhas been shown to specifically protect normal tissues from damage caused by \nradiation and chemotherapy. An inactive prodrug, amifostine is converted to an \nactive thiol by dephosphorylation by alkaline phosphatase in the normal \nendothelium. The hypovascularity and acidity of the tumor environment and the \ndifferential expression of alkaline phosphatase in normal and neoplastic tissues \ncontribute to its cytoprotective selectivity. The cytoprotective mechanism of \namifostine is complicated, involving free-radical scavenging, DNA protection and \nrepair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug \nAdministration has approved the i.v. use of amifostine to reduce the cumulative \nrenal toxicity associated with repeated administration of cisplatin in patients \nwith advanced ovarian cancer and to reduce the incidence of moderate to severe \nxerostomia in patients undergoing postoperative radiation treatment for head and \nneck cancer, where the radiation port includes a substantial portion of the \nparotid glands. Nonetheless, amifostine has potential applications in many other \noncologic settings. Novel schedules and routes of administration are under \ninvestigation and may further simplify the use of amifostine, reduce any \nundesired effects, and considerably broaden its applications. This review \nsummarizes the clinical experience with amifostine and provides insight into \nfuture clinical directions.",
"Amifostine (WR-2721, Ethyol(TM)) is a chemo-and radioprotective agent which is \nincreasingly used in clinical practice to minimize antitumor therapy-induced \ntoxicities. The key of this property of amifostine is certainly its selective \naction in terms of differential protection of normal tissue and not of tumor \ncells. Using HUVEC cells and three different cancer cell lines (A549 non-small \ncell lung cancer, DND-1A melanoma and HeLa cervical carcinoma) we provide \nevidence that amifostine could protect normal, and not cancer cells, from \ncisplatin (CDDP)-induced cytotoxicity in vitro. Furthermore, low doses of \namifostine, easily attainable in vivo, can protect 50% of normal cells in vitro \nfrom CDDP-induced cytotoxicity.",
"BACKGROUND: Amifostine (WR-2721, delivered as Ethyol) is a phosphorylated \naminothiol compound clinically used in addition to cis-platinum to reduce the \ntoxic side effects of therapeutic treatment on normal cells without reducing \ntheir efficacy on tumour cells. Its mechanism of action is attributed to the \nfree radical scavenging properties of its active dephosphorylated metabolite \nWR-1065. However, amifostine has also been described as a potent hypoxia-mimetic \ncompound and as a strong p53 inducer; both effects are known to potently \nmodulate vascular endothelial growth factor (VEGF-A) expression. The angiogenic \nproperties of this drug have not been clearly defined.\nMETHODS: Cancer cell lines and endothelial cells were used in culture and \ntreated with Amifostine in order to study (i) the expression of angiogenesis \nrelated genes and proteins and (ii) the effects of the drug on VEGF-A induced in \nvitro angiogenesis.\nRESULTS: We demonstrated that the treatment of several human cancer cell lines \nwith therapeutical doses of WR-1065 led to a strong induction of different \nVEGF-A mRNA isoforms independently of HIF-1alpha. VEGF-A induction by WR-1065 \ndepends on the activation of the eIF2alpha/ATF4 pathway. This up-regulation of \nVEGF-A mRNA was accompanied by an increased secretion of VEGF-A proteins fully \nactive in stimulating vascular endothelial cells (EC). Nevertheless, direct \ntreatment of EC with amifostine impaired their ability to respond to exogenous \nVEGF-A, an effect that correlated to the down-regulation of VEGFR-2 expression, \nto the reduction in cell surface binding of VEGF-A and to the decreased \nphosphorylation of the downstream p42/44 kinases.\nCONCLUSIONS: Taken together, our results indicate that amifostine treatment \nmodulates tumour angiogenesis by two apparently opposite mechanisms - the \nincreased VEGF-A expression by tumour cells and the inhibition of EC capacity to \nrespond to VEGF-A stimulation.",
"Amifostine (Ethyol) administered to cancer patients is rapidly cleared from \nplasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and \na T1/2 beta of 8.8 min. The result is that more than 90% of the drug has \ndisappeared from the plasma compartment 6 min after intravenous (i.v.) \nadministration. Only approximately 1% of the dose appears in the ascites. Animal \nstudies indicate that amifostine is primarily excreted in urine-approximately 6% \nof the dose is excreted in the urine as amifostine and its metabolites WR-1065 \nand disulphides-which means that a large percentage of the dose is taken up by \nthe tissues. Maximal tissue concentrations of WR-1065 and the disulphides were \nobtained between 10 and 30 min after an intraperitoneal injection of amifostine \nin mice, with the lowest concentrations in tumour tissues. Because WR-1065 gives \nprotection to normal tissues rather than rescue, the pharmacokinetic data \nindicate that amifostine must be given shortly before administration of the \ncytostatic drug or radiation from which protection is required. For these \nreasons, amifostine is given to patients as a 15-min i.v. infusion before \ncisplatin and carboplatin to protect against their dose-limiting toxicities. In \nsome regimens carboplatin is combined with three doses of amifostine because of \nthe high concentration of the active carboplatin species during the first 4 h \nafter administration. When carboplatin was administered as a 15-min i.v. \ninfusion of 400 mg/m2 and amifostine as a 15-min i.v. infusion of 740 mg/m2 just \nbefore and 2 and 4 h after carboplatin, the area under the plasma \nconcentration-time curve for ultrafilterable platinum increased from 253 +/- 45 \nmicroM.h (n = 6) for carboplatin alone to 305 +/- 63 microM.h (n = 11) for \ncarboplatin+three doses of amifostine. Experiments in nude mice bearing OVCAR-3 \nxenografts showed that amifostine, given once before cisplatin or three times in \ncombination with carboplatin, did not affect the antitumour effect of these \ndrugs. When amifostine was only given just before carboplatin, it even \nstimulated the antitumour effect of carboplatin significantly.",
"Controlled clinical trials indicate that amifostine (WR-2721, Ethyol) confers \nprotection from the cumulative hematologic toxicities associated with alkylating \nagents and organoplatinums. To determine whether amifostine protects primitive \nhematopoietic progenitors from the cytotoxicity of functionally diverse \nantineoplastics, formation of the multipotent hematopoietic progenitors \ncolony-forming units-granulocyte-erythroid, macrophage, megakaryocyte (CFU-GEMM) \nand erythroid burst-forming units (BFU-E) was evaluated using a clonogenic \nprogenitor inhibition assay. Bone marrow mononuclear cells from normal donors \nwere subjected to a 15-minute exposure of medium, amifostine (500 micromol/L), \nor WR-1065 (100 micromol/L at concentrations approximating peak plasma levels, \nwashed twice, then treated with the antineoplastic for 1 to 6 hours. Colony \ngrowth was scored after 14 days of incubation. Amifostine conferred protection \nagainst a broader range of antineoplastics than did WR-1065. Amifostine \nprotected CFU-GEMM against cytotoxicity from daunorubicin, mitoxantrone, and \npaclitaxel (range, 1.29- to 9.57-fold) (P < .05) but did not afford protection \nagainst cisplatin, diaziquone, or thiotepa. Similarly, amifostine protected \nBFU-E against toxicity from doxorubicin, mitoxantrone, paclitaxel, cisplatin, \nand diaziquone, yielding 3.4- to 65-fold greater colony recovery compared with \ncontrols. The high degree of cytoprotection afforded by amifostine derived \nlargely from stimulation of progenitor growth at sublethal chemotherapy \nconcentrations. In the absence of antineoplastic exposure, preincubation with \namifostine or WR-1065 enhanced the colony-forming capacity of bone marrow \nprogenitors from six normal donors, increasing recovery of CFU-GEMM and BFU-E up \nto sevenfold. We conclude that amifostine protects primitive hematopoietic \nprogenitors from a wide range of antineoplastics. This broad hemoprotective \neffect derives in part from inherent trophic effects on progenitor growth and \nsurvival.",
"PURPOSE: The cytoprotective mechanism of amifostine (WR-2721) implies free \nradical scavenging and DNA repair activities. We investigated additional \ncytoprotective pathways involving intracellular hypoxia and the activation of \nthe hypoxia-inducible factor (HIF) pathway, a key transcription factor \nregulating glycolysis, angiogenesis and apoptosis, which is also linked with \nradioresistance.\nMATERIALS AND METHODS: The glucose and oxygen levels in the peripheral blood of \npatients receiving 1000 mg amifostine were determined at various time-points in \norder to investigate the metabolic changes induced by amifostine. MDA468 breast \ntumor cell lines were incubated with a high amifostine concentration (10 m M) to \novercome the natural resistance of cancer cells to influx of the non-hydrolyzed \nWR-2721, and the HIF1 alpha protein levels were determined by Western blot \nanalysis. In vivo experiments with Wistar rats were performed in order to assess \nimmunohistochemically changes in the intracellular accumulation of HIF1 alpha \ninduced by amifostine (200 mg/kg).\nRESULTS: By 30 min following amifostine administration, the hemoglobin oxygen \nsaturation and pO(2) levels had increased in the peripheral blood while glucose \nlevels had reduced, providing evidence that normal tissue metabolism switches to \nglycolytic pathways. Incubation of cell lines with amifostine resulted in HIF1 \nalpha induction. In Wistar rats administration of amifostine resulted in \nincreased HIF1 alpha accumulation in normal tissues.\nCONCLUSIONS: Since it is doubtful whether dephosphorylation of amifostine to the \nactive metabolite WR-1065 occurs within tumoral tissues (an acidic environment \nthat lacks vascular alkaline phosphatase activity), intracellular hypoxia and \nupregulation of HIF1 alpha represents an additional, normal tissue-specific, \namifostine cytoprotective pathway.",
"Intrinsic radioresistance, tumor hypoxia and ability of cancer cells to undergo \nrapid repopulation during radiotherapy are associated with failure of \nradiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable \nto undergo re-oxygenation, are unlikely to be eradicated with standard \nradiotherapy. Although the therapeutic efficacy of accelerated regimens based on \nlow-dose per fraction may be high since they minimize the adverse role of rapid \ntumor repopulation, the cellular compartment with low alpha/beta-ratio values \n(i.e. hypoxic cells) remains a limiting factor. Accelerated hypofractionation, \nwhich may be more effective in such tumors, cannot be safely applied unless \nnormal tissues are protected. In the present study we assessed the feasibility \nof hypofractionated and accelerated radiotherapy supported by cytoprotection \n(HypoARC) with high dose daily amifostine. Fifteen breast cancer patients with \nlocally advanced disease entered radiation-dose escalation protocoL Twelve \nconsecutive fractions of 3.5-4Gy (5 fractions/week) were given to the \nbreast/chest wall, supraclavicular and axillary area, within 17 days. A high \ndose of amifostine, at 1,000 mg flat dose, was given 20 minutes before each \nradiotherapy fraction. Amifostine administration was well- tolerated with minor \nside-effects (vomiting in 6 out of 15 and hypotention in 2 out of 15 patients). \nRadiation induced acute skin toxicity was negligible (grade 3 in 1 out of 15 \npatients). Ten out of 15 patients survived more than 12 months and 7 out of 15 \nmore than 18 months following HypoARC. None of these patients showed any signs \nof late sequellae, such as lung and myoskeletal fibrosis, or brachial \nplexopathy. Complete and partial responses were obtained in 11 out of 15 (73%) \nand in 4 out of 15 (27%) patients, respectively. High dose daily amifostine \nduring hypofractionated radiotherapy is feasible. HypoARC regimen is \nwell-tolerated, effective and has minimal acute and late toxicity to normal \nbreast, chest and axillary tissues.",
"Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum \ncytoprotector of normal tissues that provides cytoprotection against ionizing \nradiation and chemotherapeutic agents, thus preserving the efficacy of \nradiotherapy and chemotherapy. This review summarizes the preclinical data and \nclinical experience with amifostine, and provides insight into future clinical \ndirections. Amifostine, an inactive pro-drug, is transformed to an active thiol \nafter dephosphorylation by alkaline phosphatase found in the normal endothelium. \nThe absence of alkaline phosphatase in the tumoral endothelium and stromal \ncomponents, and the hypovascularity and acidity of the tumor environment, may \nexplain its cytoprotective selectivity. The cytoprotective mechanism of \namifostine is complicated, involving free radical scavenging, DNA protection and \nrepair acceleration, and induction of cellular hypoxia. Intravenous \nadministration of amifostine 740-900 mg/m(2) before chemotherapy and 250-350 \nmg/m(2) before each radiotherapy fraction are widely used regimens. The US Food \nand Drug Administration has approved the use of amifostine as a cytoprotector \nfor cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials \nare being conducted to determine the efficacy of amifostine in reducing \nradiation-induced mucositis and other toxicities. Novel schedules and routes of \nadministration are under investigation, and may further simplify the use of \namifostine and considerably broaden its applications."
] | ['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0071456', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015687', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0001666', 'http://www.biosemantics.org/jochem#4217067', 'http://www.biosemantics.org/jochem#4277891', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000860', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004999'] |
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] | train | Why graphics processing units (GPU) are more suitable for biological tasks than central processing units (CPU)? | summary | Traditional central processing unist (CPUs) are reaching their limit in processing power and are not designed primarily for multithreaded applications. Graphics processing units (GPUs) on the other hand are affordable, scalable computer powerhouses that, thanks to the ever increasing demand for higher quality graphics, have yet to reach their limit. Typically high-end CPUs have 8-16 cores, whereas GPUs can have more than 2,500 cores. GPUs are also, by design, highly parallel, multicore and multithreaded, able of handling thousands of threads doing the same calculation on different subsets of a large data set. This ability is what makes them perfectly suited for biological analysis tasks. Lately this potential has been realized by many bioinformatics researches and a huge variety of tools and algorithms have been ported to GPUs, or designed from the ground up to maximize the usage
of available cores. | Traditional central processing unist (CPUs) are reaching their limit in processing power and are not designed primarily for multithreaded applications. Graphics processing units (GPUs) on the other hand are affordable, scalable computer powerhouses that, thanks to the ever increasing demand for higher quality graphics, have yet to reach their limit. Typically high-end CPUs have 8-16 cores, whereas GPUs can have more than 2,500 cores. GPUs are also, by design, highly parallel, multicore and multithreaded, able of handling thousands of threads doing the same calculation on different subsets of a large data set. This ability is what makes them perfectly suited for biological analysis tasks. Lately this potential has been realized by many bioinformatics researches and a huge variety of tools and algorithms have been ported to GPUs, or designed from the ground up to maximize the usage
of available cores. | [
"We investigate the potential in using of using a graphics processor unit (GPU) \nfor Monte-Carlo (MC)-based radiation dose calculations. The percent depth dose \n(PDD) of photons in a medium with known absorption and scattering coefficients \nis computed using a MC simulation running on both a standard CPU and a GPU. We \ndemonstrate that the GPU's capability for massive parallel processing provides a \nsignificant acceleration in the MC calculation, and offers a significant \nadvantage for distributed stochastic simulations on a single computer. \nHarnessing this potential of GPUs will help in the early adoption of MC for \nroutine planning in a clinical environment.",
"PURPOSE: List-mode processing is an efficient way of dealing with the sparse \nnature of positron emission tomography (PET) data sets and is the processing \nmethod of choice for time-of-flight (ToF) PET image reconstruction. However, the \nmassive amount of computation involved in forward projection and backprojection \nlimits the application of list-mode reconstruction in practice, and makes it \nchallenging to incorporate accurate system modeling.\nMETHODS: The authors present a novel formulation for computing line projection \noperations on graphics processing units (GPUs) using the compute unified device \narchitecture (CUDA) framework, and apply the formulation to list-mode \nordered-subsets expectation maximization (OSEM) image reconstruction. Our method \novercomes well-known GPU challenges such as divergence of compute threads, \nlimited bandwidth of global memory, and limited size of shared memory, while \nexploiting GPU capabilities such as fast access to shared memory and efficient \nlinear interpolation of texture memory. Execution time comparison and image \nquality analysis of the GPU-CUDA method and the central processing unit (CPU) \nmethod are performed on several data sets acquired on a preclinical scanner and \na clinical ToF scanner.\nRESULTS: When applied to line projection operations for non-ToF list-mode PET, \nthis new GPU-CUDA method is >200 times faster than a single-threaded reference \nCPU implementation. For ToF reconstruction, we exploit a ToF-specific \noptimization to improve the efficiency of our parallel processing method, \nresulting in GPU reconstruction >300 times faster than the CPU counterpart. For \na typical whole-body scan with 75 × 75 × 26 image matrix, 40.7 million LORs, 33 \nsubsets, and 3 iterations, the overall processing time is 7.7 s for GPU and 42 \nmin for a single-threaded CPU. Image quality and accuracy are preserved for \nmultiple imaging configurations and reconstruction parameters, with normalized \nroot mean squared (RMS) deviation less than 1% between CPU and GPU-generated \nimages for all cases.\nCONCLUSIONS: A list-mode ToF OSEM library was developed on the GPU-CUDA \nplatform. Our studies show that the GPU reformulation is considerably faster \nthan a single-threaded reference CPU method especially for ToF processing, while \nproducing virtually identical images. This new method can be easily adapted to \nenable more advanced algorithms for high resolution PET reconstruction based on \nadditional information such as depth of interaction (DoI), photon energy, and \npoint spread functions (PSFs).",
"To evaluate the use of general-purpose graphics processing units (GPGPUs) to \nimprove the performance of MODFLOW, an unstructured preconditioned conjugate \ngradient (UPCG) solver has been developed. The UPCG solver uses a compressed \nsparse row storage scheme and includes Jacobi, zero fill-in incomplete, and \nmodified-incomplete lower-upper (LU) factorization, and generalized \nleast-squares polynomial preconditioners. The UPCG solver also includes options \nfor sequential and parallel solution on the central processing unit (CPU) using \nOpenMP. For simulations utilizing the GPGPU, all basic linear algebra operations \nare performed on the GPGPU; memory copies between the central processing unit \nCPU and GPCPU occur prior to the first iteration of the UPCG solver and after \nsatisfying head and flow criteria or exceeding a maximum number of iterations. \nThe efficiency of the UPCG solver for GPGPU and CPU solutions is benchmarked \nusing simulations of a synthetic, heterogeneous unconfined aquifer with tens of \nthousands to millions of active grid cells. Testing indicates GPGPU speedups on \nthe order of 2 to 8, relative to the standard MODFLOW preconditioned conjugate \ngradient (PCG) solver, can be achieved when (1) memory copies between the CPU \nand GPGPU are optimized, (2) the percentage of time performing memory copies \nbetween the CPU and GPGPU is small relative to the calculation time, (3) \nhigh-performance GPGPU cards are utilized, and (4) CPU-GPGPU combinations are \nused to execute sequential operations that are difficult to parallelize. \nFurthermore, UPCG solver testing indicates GPGPU speedups exceed parallel CPU \nspeedups achieved using OpenMP on multicore CPUs for preconditioners that can be \neasily parallelized.",
"MOTIVATION: The importance of stochasticity in biological systems is becoming \nincreasingly recognized and the computational cost of biologically realistic \nstochastic simulations urgently requires development of efficient software. We \npresent a new software tool STOCHSIMGPU that exploits graphics processing units \n(GPUs) for parallel stochastic simulations of biological/chemical reaction \nsystems and show that significant gains in efficiency can be made. It is \nintegrated into MATLAB and works with the Systems Biology Toolbox 2 (SBTOOLBOX2) \nfor MATLAB.\nRESULTS: The GPU-based parallel implementation of the Gillespie stochastic \nsimulation algorithm (SSA), the logarithmic direct method (LDM) and the next \nreaction method (NRM) is approximately 85 times faster than the sequential \nimplementation of the NRM on a central processing unit (CPU). Using our software \ndoes not require any changes to the user's models, since it acts as a direct \nreplacement of the stochastic simulation software of the SBTOOLBOX2.\nAVAILABILITY: The software is open source under the GPL v3 and available at \nhttp://www.maths.ox.ac.uk/cmb/STOCHSIMGPU. The web site also contains \nsupplementary information.\nCONTACT: klingbeil@maths.ox.ac.uk\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics \nonline.",
"Theoretical exploration of fundamental biological processes involving the forced \nunraveling of multimeric proteins, the sliding motion in protein fibers and the \nmechanical deformation of biomolecular assemblies under physiological force \nloads is challenging even for distributed computing systems. Using a C(α)-based \ncoarse-grained self organized polymer (SOP) model, we implemented the Langevin \nsimulations of proteins on graphics processing units (SOP-GPU program). We \nassessed the computational performance of an end-to-end application of the \nprogram, where all the steps of the algorithm are running on a GPU, by profiling \nthe simulation time and memory usage for a number of test systems. The ∼90-fold \ncomputational speedup on a GPU, compared with an optimized central processing \nunit program, enabled us to follow the dynamics in the centisecond timescale, \nand to obtain the force-extension profiles using experimental pulling speeds \n(v(f) = 1-10 μm/s) employed in atomic force microscopy and in optical \ntweezers-based dynamic force spectroscopy. We found that the mechanical \nmolecular response critically depends on the conditions of force application and \nthat the kinetics and pathways for unfolding change drastically even upon a \nmodest 10-fold increase in v(f). This implies that, to resolve accurately the \nfree energy landscape and to relate the results of single-molecule experiments \nin vitro and in silico, molecular simulations should be carried out under the \nexperimentally relevant force loads. This can be accomplished in reasonable \nwall-clock time for biomolecules of size as large as 10(5) residues using the \nSOP-GPU package.",
"BACKGROUND: Many important biological problems can be modeled as contagion \ndiffusion processes over interaction networks. This article shows how the \nEpiSimdemics interaction-based simulation system can be applied to the general \ncontagion diffusion problem. Two specific problems, computational epidemiology \nand human immune system modeling, are given as examples. We then show how the \ngraphics processing unit (GPU) within each compute node of a cluster can \neffectively be used to speed-up the execution of these types of problems.\nRESULTS: We show that a single GPU can accelerate the EpiSimdemics computation \nkernel by a factor of 6 and the entire application by a factor of 3.3, compared \nto the execution time on a single core. When 8 CPU cores and 2 GPU devices are \nutilized, the speed-up of the computational kernel increases to 9.5. When \ncombined with effective techniques for inter-node communication, excellent \nscalability can be achieved without significant loss of accuracy in the results.\nCONCLUSIONS: We show that interaction-based simulation systems can be used to \nmodel disparate and highly relevant problems in biology. We also show that \noffloading some of the work to GPUs in distributed interaction-based simulations \ncan be an effective way to achieve increased intra-node efficiency.",
"BACKGROUND: The recent availability of new, less expensive high-throughput DNA \nsequencing technologies has yielded a dramatic increase in the volume of \nsequence data that must be analyzed. These data are being generated for several \npurposes, including genotyping, genome resequencing, metagenomics, and de novo \ngenome assembly projects. Sequence alignment programs such as MUMmer have proven \nessential for analysis of these data, but researchers will need ever faster, \nhigh-throughput alignment tools running on inexpensive hardware to keep up with \nnew sequence technologies.\nRESULTS: This paper describes MUMmerGPU, an open-source high-throughput parallel \npairwise local sequence alignment program that runs on commodity Graphics \nProcessing Units (GPUs) in common workstations. MUMmerGPU uses the new Compute \nUnified Device Architecture (CUDA) from nVidia to align multiple query sequences \nagainst a single reference sequence stored as a suffix tree. By processing the \nqueries in parallel on the highly parallel graphics card, MUMmerGPU achieves \nmore than a 10-fold speedup over a serial CPU version of the sequence alignment \nkernel, and outperforms the exact alignment component of MUMmer on a high end \nCPU by 3.5-fold in total application time when aligning reads from recent \nsequencing projects using Solexa/Illumina, 454, and Sanger sequencing \ntechnologies.\nCONCLUSION: MUMmerGPU is a low cost, ultra-fast sequence alignment program \ndesigned to handle the increasing volume of data produced by new, \nhigh-throughput sequencing technologies. MUMmerGPU demonstrates that even \nmemory-intensive applications can run significantly faster on the relatively \nlow-cost GPU than on the CPU.",
"There is currently a strong push in the research community to develop biological \nscale implementations of neuron based vision models. Systems at this scale are \ncomputationally demanding and generally utilize more accurate neuron models, \nsuch as the Izhikevich and the Hodgkin-Huxley models, in favor of the more \npopular integrate and fire model. We examine the feasibility of using graphics \nprocessing units (GPUs) to accelerate a spiking neural network based character \nrecognition network to enable such large scale systems. Two versions of the \nnetwork utilizing the Izhikevich and Hodgkin-Huxley models are implemented. \nThree NVIDIA general-purpose (GP) GPU platforms are examined, including the \nGeForce 9800 GX2, the Tesla C1060, and the Tesla S1070. Our results show that \nthe GPGPUs can provide significant speedup over conventional processors. In \nparticular, the fastest GPGPU utilized, the Tesla S1070, provided a speedup of \n5.6 and 84.4 over highly optimized implementations on the fastest central \nprocessing unit (CPU) tested, a quadcore 2.67 GHz Xeon processor, for the \nIzhikevich and the Hodgkin-Huxley models, respectively. The CPU implementation \nutilized all four cores and the vector data parallelism offered by the \nprocessor. The results indicate that GPUs are well suited for this application \ndomain.",
"An efficient graphics processing units (GPUs) version of time-dependent \nwavepacket code is developed for the atom-diatom state-to-state reactive \nscattering processes. The propagation of the wavepacket is entirely calculated \non GPUs employing the split-operator method after preparation of the initial \nwavepacket on the central processing unit (CPU). An additional split-operator \nmethod is introduced in the rotational part of the Hamiltonian to decrease \ncommunication of GPUs without losing accuracy of state-to-state information. The \ncode is tested to calculate the differential cross sections of H + H2 reaction \nand state-resolved reaction probabilities of nonadiabatic triplet-singlet \ntransitions of O((3)P,(1)D) + H2 for the total angular momentum J = 0. The \nglobal speedups of 22.11, 38.80, and 44.80 are found comparing the parallel \ncomputation of one GPU, two GPUs by exact rotational operator, and two GPU \nversions by an approximate rotational operator with serial computation of the \nCPU, respectively.",
"BACKGROUND: Protein-DNA docking is a very challenging problem in structural \nbioinformatics and has important implications in a number of applications, such \nas structure-based prediction of transcription factor binding sites and rational \ndrug design. Protein-DNA docking is very computational demanding due to the high \ncost of energy calculation and the statistical nature of conformational sampling \nalgorithms. More importantly, experiments show that the docking quality depends \non the coverage of the conformational sampling space. It is therefore desirable \nto accelerate the computation of the docking algorithm, not only to reduce \ncomputing time, but also to improve docking quality.\nMETHODS: In an attempt to accelerate the sampling process and to improve the \ndocking performance, we developed a graphics processing unit (GPU)-based \nprotein-DNA docking algorithm. The algorithm employs a potential-based energy \nfunction to describe the binding affinity of a protein-DNA pair, and integrates \nMonte-Carlo simulation and a simulated annealing method to search through the \nconformational space. Algorithmic techniques were developed to improve the \ncomputation efficiency and scalability on GPU-based high performance computing \nsystems.\nRESULTS: The effectiveness of our approach is tested on a non-redundant set of \n75 TF-DNA complexes and a newly developed TF-DNA docking benchmark. We \ndemonstrated that the GPU-based docking algorithm can significantly accelerate \nthe simulation process and thereby improving the chance of finding near-native \nTF-DNA complex structures. This study also suggests that further improvement in \nprotein-DNA docking research would require efforts from two integral aspects: \nimprovement in computation efficiency and energy function design.\nCONCLUSIONS: We present a high performance computing approach for improving the \nprediction accuracy of protein-DNA docking. The GPU-based docking algorithm \naccelerates the search of the conformational space and thus increases the chance \nof finding more near-native structures. To the best of our knowledge, this is \nthe first ad hoc effort of applying GPU or GPU clusters to the protein-DNA \ndocking problem.",
"The study was to explore the power and feasibility of using programmable \ngraphics processing units (GPUs) for real-time rendering and displaying large 3D \nmedical datasets for stereoscopic display workstation. Lung cancer screening CT \nimages were used for developing GPU-based stereo rendering and displaying. The \nstudy was run on a personal computer with a 128 MB NVIDIA Quadro FX 1100 \ngraphics card. The performance of rendering and displaying was measured and \ncompared between GPU-based and central processing unit (CPU)-based programming. \nThe results indicate that GPU-based programming was capable of rendering large \n3D datasets at real-time interactive rates with stereographic displays."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D003196'] |
6053be3594d57fd879000019 | [
31110049
] | train | Why is fingolimod considered a prodrug? | summary | FTY720/fingolimod, is considered a prodrug because it requires in vivo phosphorylation to its active phosphorylated form. | FTY720/fingolimod, is considered a prodrug because it requires in vivo phosphorylation to its active phosphorylated form. | [
"Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, \nis a metabolic disease that begins with steatosis. Sphingolipid metabolites, \nparticularly ceramide and sphingosine-1-phosphate (S1P), have recently received \nattention for their potential roles in insulin resistance and hepatic steatosis. \nFTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is \nphosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 \nand has been shown to interfere with the actions of S1P and to inhibit ceramide \nbiosynthesis. Therefore, in this study we investigated the effects of FTY720 in \na diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks \nof the human disease. The oral administration of FTY720 to these mice fed a \nhigh-fat diet and sugar water improved glucose tolerance and reduced steatosis. \nIn addition to decreasing liver triglycerides, FTY720 also reduced hepatic \nsphingolipid levels, including ceramides, monohexosylceramides, and \nsphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and \ndihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase \n(FASN) expression in DIAMOND mice without affecting other key enzymes in \nlipogenesis. FTY720 had no effect on the expression of SREBP-1c, which \ntranscriptionally activates FASN. However, in agreement with the notion that the \nactive phosphorylated form of FTY720 is an inhibitor of histone deacetylases, \nFTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly \nincreased in these mice. Hence, FTY720 might be useful for attenuating FASN \nexpression and triglyceride accumulation associated with steatosis."
] | nan |
530b01a6970c65fa6b000008 | [
21133379,
21953191,
16249172,
22941912,
16478717
] | train | Why is lock mass used in Orbitrap measurements? | summary | The lock mass is a compound of known mass and is used to compensate for drifts in instrument calibration. | The lock mass is a compound of known mass and is used to compensate for drifts in instrument calibration. | [
"The positive role and application of highly accurate mass measurements in \nproteomics is well documented. The new generation of hybrid FTMS and Q-TOF \ninstruments, including the LTQ-Orbitrap (OT), is remarkable in their ability to \nroutinely produce single-digit to subppm statistical mass accuracy while \nmaintaining high analytical sensitivity. The use of mass calibrants (lock \nmasses) to reduce the systematic error of mass-to-charge measurements has also \nbeen reported and, in some cases, incorporated in the instrument control \nsoftware by the instrument manufacturers. We evaluated the use of one such \ncalibrant in the OT (e.g., polydimethylcyclosiloxane, PCM) to study its impact \non the rate of phosphopeptide annotation and found it to lack robustness under \nnormal laboratory conditions. Therefore, we devised a strategy to improve its \nperformance by increasing the external abundance of calibrant molecules in \nlaboratory air. This resulted in a more robust performance of the preprogrammed \nlock mass recalibration feature as evidenced by improvements in both statistical \nmass accuracy and peptide annotation rates.",
"Mass accuracy is a key parameter in proteomic experiments, improving \nspecificity, and success rates of peptide identification. Advances in \ninstrumentation now make it possible to routinely obtain high resolution data in \nproteomic experiments. To compensate for drifts in instrument calibration, a \ncompound of known mass is often employed. This 'lock mass' provides an internal \nmass standard in every spectrum. Here we take advantage of the complexity of \ntypical peptide mixtures in proteomics to eliminate the requirement for a \nphysical lock mass. We find that mass scale drift is primarily a function of the \nm/z and the elution time dimensions. Using a subset of high confidence peptide \nidentifications from a first pass database search, which effectively substitute \nfor the lock mass, we set up a global mathematical minimization problem. We \nperform a simultaneous fit in two dimensions using a function whose \nparameterization is automatically adjusted to the complexity of the analyzed \npeptide mixture. Mass deviation of the high confidence peptides from their \ncalculated values is then minimized globally as a function of both m/z value and \nelution time. The resulting recalibration function performs equal or better than \nadding a lock mass from laboratory air to LTQ-Orbitrap spectra. This 'software \nlock mass' drastically improves mass accuracy compared with mass measurement \nwithout lock mass (up to 10-fold), with none of the experimental cost of a \nphysical lock mass, and it integrated into the freely available MaxQuant \nanalysis pipeline ( www.maxquant.org ).",
"Mass accuracy is a key parameter of mass spectrometric performance. TOF \ninstruments can reach low parts per million, and FT-ICR instruments are capable \nof even greater accuracy provided ion numbers are well controlled. Here we \ndemonstrate sub-ppm mass accuracy on a linear ion trap coupled via a radio \nfrequency-only storage trap (C-trap) to the orbitrap mass spectrometer (LTQ \nOrbitrap). Prior to acquisition of a spectrum, a background ion originating from \nambient air is first transferred to the C-trap. Ions forming the MS or MS(n) \nspectrum are then added to this species, and all ions are injected into the \norbitrap for analysis. Real time recalibration on the \"lock mass\" by corrections \nof mass shift removes mass error associated with calibration of the mass scale. \nThe remaining mass error is mainly due to imperfect peaks caused by weak signals \nand is addressed by averaging the mass measurement over the LC peak, weighted by \nsignal intensity. For peptide database searches in proteomics, we introduce a \nvariable mass tolerance and achieve average absolute mass deviations of 0.48 ppm \n(standard deviation 0.38 ppm) and maximal deviations of less than 2 ppm. For \ntandem mass spectra we demonstrate similarly high mass accuracy and discuss its \nimpact on database searching. High and routine mass accuracy in a compact \ninstrument will dramatically improve certainty of peptide and small molecule \nidentification.",
"A recent trend in the use of high resolution accurate mass screening (HRAMS) for \ndoping control testing in both human and animal sports has emerged due to \nsignificant improvement in high resolution mass spectrometry in terms of \nsensitivity, mass accuracy, mass resolution, and mass stability. A number of \nHRAMS methods have been reported for the detection of multi-drug residues in \nhuman or equine urine. As blood has become a common matrix for doping control \nanalysis, especially in equine sports, a sensitive, fast and wide coverage \nscreening method for detecting a large number of drugs in equine blood samples \nwould be desirable. This paper presents the development of a liquid \nchromatography-high resolution mass spectrometry (LC-HRMS) screening method for \nequine plasma samples to cover over 320 prohibited substances in a single \nanalytical run. Plasma samples were diluted and processed by solid-phase \nextraction. The extracts were then analyzed with LC-HRMS in full-scan positive \nelectrospray ionization mode. A mass resolution of 60 000 was employed. \nBenzyldimethylphenylammonium was used as an internal lock mass. Drug targets \nwere identified by retention time and accurate mass, with a mass tolerance \nwindow of ±3 ppm. Over 320 drug targets could be detected in a 13-min run. \nValidation data including sensitivity, specificity, extraction recovery and \nprecision are presented. As the method employs full-scan mass spectrometry, an \nunlimited number of drug targets can theoretically be incorporated. Moreover, \nthe HRAMS data acquired can be re-processed retrospectively to search for drugs \nwhich have not been targeted at the time of analysis.",
"Top-down proteomics, the analysis of intact proteins (instead of first digesting \nthem to peptides), has the potential to become a powerful tool for mass \nspectrometric protein characterization. Requirements for extremely high mass \nresolution, accuracy, and ability to efficiently fragment large ions have often \nlimited top-down analyses to custom built FT-ICR mass analyzers. Here we explore \nthe hybrid linear ion trap (LTQ)-Orbitrap, a novel, high performance, and \ncompact mass spectrometric analyzer, for top-down proteomics. Protein standards \nfrom 10 to 25 kDa were electrosprayed into the instrument using a \nnanoelectrospray chip. Resolving power of 60,000 was ample for isotope \nresolution of all protein charge states. We achieved absolute mass accuracies \nfor intact proteins between 0.92 and 2.8 ppm using the \"lock mass\" mode of \noperation. Fifty femtomole of cytochrome c applied to the chip resulted in \nspectra with excellent signal-to-noise ratio and only low attomole sample \nconsumption. Different protein charge states were dissociated in the LTQ, and \nthe sensitivity of the orbitrap allowed routine, high resolution, and high mass \naccuracy fragment detection. This resulted in unambiguous charge state \ndetermination of fragment ions and identification of unmodified and modified \nproteins by database searching. Protein fragments were further isolated and \nfragmented in the LTQ followed by analysis of MS(3) fragments in the orbitrap, \nlocalizing modifications to part of the sequence and helping to identify the \nprotein with these small peptide-like fragments. Given the ready availability \nand ease of operation of the LTQ-Orbitrap, it may have significant impact on \ntop-down proteomics."
] | ['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D013058'] |
5a774431faa1ab7d2e000004 | [
28709498
] | train | Why is the Fyn kinase considered a promising therapeutic target for Alzheimer's Disease? | summary | Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. | Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. | [
"The past decade has brought tremendous progress in unraveling the \npathophysiology of Alzheimer's disease (AD). While increasingly sophisticated \nimmunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues \nto dominate clinical research in AD, a deeper understanding of Aβ physiology has \nled to the recognition of distinct neuronal signaling pathways linking Aβ to \nsynaptotoxicity and neurodegeneration and to new targets for therapeutic \nintervention. Identifying specific signaling pathways involving Aβ has allowed \nfor the development of more precise therapeutic interventions targeting the most \nrelevant molecular mechanisms leading to AD. In this review, I highlight the \ndiscovery of cellular prion protein as a high-affinity receptor for Aβ \noligomers, and the downstream signaling pathway elucidated to date, converging \non nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn \nas a therapeutic intervention in AD and our recent experience with the safety, \ntolerability, and cerebrospinal fluid penetration of the Src family kinase \ninhibitor saracatinib in patients with AD. Fyn is an attractive target for AD \ntherapeutics, not only based on its activation by Aβ via cellular prion protein \nbut also due to its known interaction with tau, uniquely linking the two key \npathologies in AD. Fyn is also a challenging target, with broad expression \nthroughout the body and significant homology with other members of the Src \nfamily kinases, which may lead to unintended off-target effects. A phase 2a \nproof-of-concept clinical trial in patients with AD is currently under way, \nproviding critical first data on the potential effectiveness of targeting Fyn in \nAD."
] | nan |
62058382c9dfcb9c09000031 | [
31828807
] | train | Why mix γ-cyclodextrin with grapefruit juice? | summary | Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug-grapefruit juice interaction. The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD.The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug-grapefruit juice interactions. | Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug-grapefruit juice interaction. The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD.The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug-grapefruit juice interactions. | [
"OBJECTIVES: Grapefruit (Citrus paradisi) juice enhances the oral bioavailability \nof drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). \nPatients are advised to avoid drinking grapefruit juice to prevent this \ndrug-grapefruit juice interaction. The aim of this study was to investigate \nwhether processing grapefruit juice with cyclodextrins (CDs) would result in \npreventing or inhibiting this interaction.\nMETHODS: Grapefruit juice and the major furanocoumarins found in grapefruit, \nbergamottin (BG) and 6', 7'-dihydroxy bergamottin (DHBG) were mixed with α, β \nand γCDs. The effects of these processed juice samples and furanocoumarins on \nCYP3A activity were compared with the corresponding values for unprocessed \njuices and furanocoumarins. Interactions between CDs and these furanocoumarins \nwere also investigated by phase solubility and 1 H NMR studies.\nKEY FINDINGS: The inhibition of CYP3A by grapefruit juice was significantly \nattenuated by processing particularly with γCD. Similar attenuation effects by \nγCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were \nsuggested to be strongly encapsulated in the cavity of γCD.\nCONCLUSION: The encapsulation of BG and DHBG by γCD and the resulting \nattenuation of the inhibition of CYP3A activity by grapefruit juice may be \napplicable to juice processing for preventing drug-grapefruit juice \ninteractions."
] | nan |
606ad4bd94d57fd879000054 | [
28696420
] | train | Why mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding? | summary | Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. | Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. | [
"Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants \nto risk of adverse events when taking codeine while breastfeeding, by producing \nmore of the active metabolite, morphine. Pharmacogenetic testing may be a \nvaluable tool to identify such mothers, but testing can be costly. The objective \nof the study was to determine the incremental costs of genotyping to avert \nneonatal adverse events during maternal pharmacotherapy. A cost-effectiveness \nanalysis, using a decision model, was performed with a hypothetical cohort of \nprenatal subjects. Parameter estimates, costs and ranges for sensitivity \nanalyses were ascertained from the literature and expert opinion. Sensitivity \nanalyses were conducted to assess the robustness of the results. Probabilistic \nsensitivity analysis revealed an incremental cost-effectiveness (ICER) of \n$10 433 (Canadian dollars) for genotyping compared to no genotyping per adverse \nevent averted. Results were sensitive to hospital admission costs. The ICER was \nlower when evaluating only subjects having caesarean deliveries or those from \nethnic populations known to have a high prevalence of ultra-rapid metabolizers. \nAlthough genotyping to guide pharmacotherapy was not cost saving, the cost to \navert an infant adverse event may represent good value for money in specific \npopulations. With a growing demand for personalized medicine, these findings are \nrelevant for decision makers, clinicians and patients."
] | nan |
5891f9e549702f2e01000002 | [
22937989,
26077324,
24992148,
25230997,
27292821,
26298776,
25301914,
24157095,
26298794,
25510187,
27481386,
22678064,
23859128,
25113274,
26429756,
24812538,
26545868,
23963470,
24001490,
26329430,
24605270,
26874840,
23397977,
26725086,
15165536,
24892899,
26329446,
26329447,
24246378,
25201131,
25093484,
24293752,
27662970
] | train | Willis-Ekbom disease is also known as? | factoid | Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common movement disorder characterized by an uncontrollable urge to move because of uncomfortable, sometimes painful sensations in the legs with a diurnal variation and a release with movement. | Restless legs syndrome | [
"BACKGROUND: Since the publication of the first European Federation of \nNeurological Societies (EFNS) guidelines in 2005 on the management of restless \nlegs syndrome (RLS; also known as Willis-Ekbom disease), there have been major \ntherapeutic advances in the field. Furthermore, the management of RLS is now a \npart of routine neurological practice in Europe. New drugs have also become \navailable, and further randomized controlled trials have been undertaken. These \nguidelines were undertaken by the EFNS in collaboration with the European \nNeurological Society and the European Sleep Research Society.\nOBJECTIVES: To provide an evidence-based update of new treatments published \nsince 2005 for the management of RLS.\nMETHODS: First, we determined what the objectives of management of primary and \nsecondary RLS should be. We developed the search strategy and conducted a review \nof the scientific literature up to 31 December 2011 (print and electronic \npublications) for the drug classes and interventions employed in RLS treatment. \nPrevious guidelines were consulted. All trials were analysed according to class \nof evidence, and recommendations made according to the 2004 EFNS criteria for \nrating.\nRECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, \npramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all \nconsidered effective for the short-term treatment for RLS. However, for the \nlong-term treatment for RLS, rotigotine is considered effective, gabapentin \nenacarbil is probably effective, and ropinirole, pramipexole and gabapentin are \nconsidered possibly effective. Cabergoline has according to our criteria a level \nA recommendation, but the taskforce cannot recommend this drug because of its \nserious adverse events.",
"Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a \ncommon sensorimotor disorder that can generally be effectively managed in the \nprimary care clinic. However, some treatment complications may arise. According \nto the recommendations of the International Restless Legs Syndrome Study Group, \nnon-ergot dopamine-receptor agonists have over the past years been one of the \nfirst-line treatments for patients with RLS/WED requiring pharmacological \ntherapy. Augmentation is the main complication of long-term dopaminergic \ntreatment of RLS/WED and is defined as an overall worsening of symptoms beyond \npretreatment levels in patients who experienced an initial positive therapeutic \nresponse. Once identified on the basis of its characteristic clinical features, \naugmentation requires careful management. In order to provide clinicians with a \ncomprehensive understanding of this common treatment complication, this review \ndiscusses the clinical features of augmentation, and its differentiation from \nmorning rebound, symptom fluctuations and natural disease progression. Reported \nincidences of augmentation in clinical trials of dopaminergic RLS/WED therapies \nare summarized. Finally, the hypothetical pathophysiology of augmentation and \nthe current recommendations for management of patients with augmented RLS/WED \nsymptoms are discussed.",
"Restless leg syndrome (RLS), also known as Willis-Ekbom disease, is a condition \nthat includes sensations such as crawling, tingling, or aching in the limbs and \ncreates an urge to move. The prevalence is estimated at 3% to 15% of the \npopulation and may present as primary RLS or secondary RLS. Secondary RLS may be \na result of some medications, iron deficiency, or conditions such as \nneuropathies, or it may be related to pregnancy. The guidelines for diagnosis, \nwhich is usually made on clinical presentation, are discussed in the article. \nMedication use is not always necessary in the management of RLS. Multiple \noptions are available and are reviewed within the article. Since 2011, two \nmedications have been approved for the treatment of RLS, and these are discussed \nin detail. Neupro (rotigotine) is a dopamine agonist available as a patch that \nhas been approved for the treatment of RLS as well as Parkinson disease. One of \nthe major issues in treating RLS with dopamine agonists is augmentation, meaning \nsymptoms occur earlier in the day due to medication use. This rate of \naugmentation with use of rotigotine is significantly lower than other dopamine \nagonists. Horizant (gabapentin enacarbil) is the only nondopaminergic medication \napproved for the treatment of RLS. Bioavailability is greater in gabapentin \nenacarbil as compared to gabapentin. Augmentation has not been associated with \ngabapentin or gabapentin enacarbil. Neupro (rotigotine) and Horizant (gabapentin \nenacarbil) provide additional treatment options for patients with RLS who are in \nneed of medications. Consideration of each individual patient is necessary when \ndetermining if medication is needed and in choosing the appropriate agent.",
"Author information:\n(1)From the Department of Preventive Medicine and Biometrics (A.I.S.), Uniformed \nServices University, Bethesda; National Institute on Aging (A.I.S., M.G., \nL.J.L.), Laboratory of Epidemiology and Population Sciences, Bethesda, MD; \nVeterans Affairs Pacific Islands Health Care System (G.W.R.), Honolulu; Pacific \nHealth Research & Education Institute (G.W.R.), Honolulu, HI; Icelandic Heart \nAssociation (S. Sigurdsson, V.G.), Kopavogur; School of Health Sciences (L.S.G.) \nand Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Department of \nNeurology (S. Sveinbjörnsdóttir), Broomfield Hospital, UK; and Department of \nPhysical Medicine and Rehabilitation (A.K.W.), University of Pittsburgh, PA. \nascher@usuhs.mil.\n(2)From the Department of Preventive Medicine and Biometrics (A.I.S.), Uniformed \nServices University, Bethesda; National Institute on Aging (A.I.S., M.G., \nL.J.L.), Laboratory of Epidemiology and Population Sciences, Bethesda, MD; \nVeterans Affairs Pacific Islands Health Care System (G.W.R.), Honolulu; Pacific \nHealth Research & Education Institute (G.W.R.), Honolulu, HI; Icelandic Heart \nAssociation (S. Sigurdsson, V.G.), Kopavogur; School of Health Sciences (L.S.G.) \nand Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Department of \nNeurology (S. Sveinbjörnsdóttir), Broomfield Hospital, UK; and Department of \nPhysical Medicine and Rehabilitation (A.K.W.), University of Pittsburgh, PA.",
"BACKGROUND: Willis-Ekbom disease/restless legs syndrome (WED/RLS) seems to be a \nfrequent cause of intractable chronic insomnia (ICI) but is under-recognized in \nchildren/adolescents with neurodevelopmental conditions (NDCs), as many patients \ndo not have the ability to express the underlying \"urge-to-move\". In light of \nthis, we aim to develop a protocol for behavioral observations supporting the \ndiagnosis of WED/RLS.\nMETHODS: We investigated 26 pediatric patients (age 1-16 years, median 8) with \nNDCs, ICI and evidence of familial WED/RLS employing (1) \"emplotted narratives\" \nfor description of the various \"urge-to-move\" presentations and (2) \nself-description and \"behavioral observations\" during a \"suggested clinical \nimmobilization test\" (SCIT).\nRESULTS: Parental narratives reflected typical WED/RLS-related \"urge-to-move\" \nsymptoms during day-, bed-, and nighttime in all patients. Fifteen out of 26 \npatients could describe the \"urge-to-move\" during the SCIT. Ten out of 26 \npatients, unable to describe their symptoms due to cognitive disabilities, \nshowed patterns of \"relieving-movements\" upon observation. Sensory processing \nabnormalities were reported in all patients, with tactile sensitivities (26/26) \n(including shifted pain threshold) as the most common sensory domain.\nCONCLUSION: \"Emplotted narratives\" and structured \"behavioral observations\" \nsupport recognition of familial WED/RLS associated movement patterns and provide \na useful tool for the diagnosis of WED/RLS in children with NDCs in a clinical \noffice setting.",
"OBJECTIVES: Willis-Ekbom disease/restless legs syndrome (WED/RLS) is the most \ncommon sleep-related movement disorder in pregnancy. We designed a prospective \nlongitudinal study to investigate the correlates of WED/RLS during and after \npregnancy.\nDESIGN: A total of 138 pregnant women with WED/RLS and a control group of 251 \nage-matched pregnant women were enrolled prospectively. A questionnaire was \nadministered during a face-to-face interview at first evaluation during \npregnancy and three months after delivery.\nRESULTS: Among all women in the first trimester, 15.6% were diagnosed with \nWED/RLS, whereas 32.8% of those in the second trimester and 38.8% of those in \nthe third trimester were diagnosed with WED/RLS (p = 0.032). In regression \nanalysis, later gestational age [p < 0.001; odds ratio (OR) 1.054] and previous \nhistory of WED/RLS (p = 0.001; OR 2.795) were positively correlated with the \npresence of WED/RLS, while ferritin levels (p = 0.001; OR 0.956) were negatively \ncorrelated with the presence of WED/RLS. Ferritin levels were also negatively \ncorrelated with the International RLS Study Group severity index (p = 0.041). \nForty-eight patients (34.8%) experienced WED/RLS symptomatology after delivery. \nThe ferritin levels were lower, and the mean number of pregnancies was higher, \nin women with residual WED/RLS (p = 0.008).\nCONCLUSION: Our survey showed that WED/RLS was more common in the second and \nthird trimesters. Emergence of WED/RLS during the second trimester was strongly \nassociated with residual WED/RLS. Lower ferritin levels were associated with \nboth WED/RLS in pregnancy and residual WED/RLS after delivery. A higher number \nof pregnancies were also associated with a greater likelihood of having residual \nWED/RLS after delivery.",
"Restless legs syndrome (RLS), recently renamed Willis-Ekbom disease (WED), is a \ncommon movement disorder. It is characterised by the need to move mainly the \nlegs due to uncomfortable, sometimes painful sensations in the legs, which have \na diurnal variation and a release with movement. Management is complex. First, \ncentres should establish the severity of RLS using a simple 10-item RLS severity \nrating scale (IRLS). They should also exclude secondary causes, in particular \nensuring normal iron levels. Mild cases can be managed by lifestyle changes, but \npatients with a IRLS score above 15 usually require pharmacological treatment. \nDopaminergic therapies remain the mainstay of medical therapies, with recent \nevidence suggesting opioids may be particularly effective. This article focuses \non the different treatment strategies in RLS, their associated complications and \nways to manage them.",
"There has been no previous side-by-side comparison of the diagnostic criteria \nfor restless legs syndrome (RLS) (Willis-Ekbom disease) and growing pains. In \nour review, we explore this comparison emphasizing overlaps and disconnects, \nsummarize recent literature exploring the relationship between the 2 entities, \nand make suggestions for future research. There is considerable overlap in the \ndiagnostic criteria for childhood RLS and growing pains. The literature also \nindicates that RLS and growing pains more commonly occur together than one would \nexpect based on chance alone, and the family histories of RLS and growing pains \noften are overlapping. Leg rubbing to obtain relief from leg discomfort is \ncommon to both disorders, though walking to obtain relief seems unique to RLS. \nChildhood RLS also has been reported to be painful in up to 45% of cases. The \ndevelopment of standard diagnostic criteria is necessary to move forward in the \nfield of growing pains research. A quantitative and validated rating scale for \ngrowing pains severity already exists. Because of the clinical and genetic \nsimilarity between RLS and growing pains, studies that parallel those previously \nperformed in RLS patients are recommended for growing pains patients. For \nexample, a genome wide association study in growing pains patients of all \npossible genes with particular attention to those identified as related to RLS \nand a therapeutic trial of medications known to be effective in RLS would be \nwelcome. Abnormalities in vitamin D metabolism also may be common to both \ndisorders.",
"BACKGROUND: Restless Legs Syndrome (RLS) or Willis-Ekbom Disease (WED) is highly \nprevalent, but patients and healthcare providers alike know little about it. \nFurthermore, controversy persists as to the best way of diagnosing this \nnosological entity.\nOBJECTIVE: To verify whether the term used to refer to this disease entity \n(Restless Legs Syndrome or Willis-Ekbom Disease) affects the prevalence of \nself-diagnosed RLS/WED in a sample of newly graduated physicians.\nMETHODS: Newly graduated physicians were asked to self-evaluate for the presence \nof RLS/WED. Briefly, participants were allocated randomly across two groups. One \nwas asked to self-assess for RLS, while the other was asked to self-assess for \nWED. The evaluation form given to one group asked 'Do you have Restless Legs \nSyndrome?' whereas the form given to participants in the other group asked 'Do \nyou have Willis-Ekbom Disease?'. Both forms also contained the four criteria for \ndiagnosing RLS proposed by the International Restless Legs Syndrome Study Group \n(IRLSSG) and instructions for self-diagnosis according to these criteria.\nRESULTS: The study sample comprised 1413 newly graduated physicians. Of the 708 \nparticipants who were given the form that used the term RLS, 87 (12.28%) \ndiagnosed themselves with the condition. Conversely, of 705 physicians given the \nform with the term WED, 13 (1.84%) diagnosed themselves with the condition \n(p <0.0001).\nCONCLUSION: A greater proportion of newly graduated physicians diagnosed \nthemselves with RLS/WED when presented with the term Restless Legs Syndrome than \nwhen presented with the term Willis-Ekbom Disease. This suggests that the term \nRestless Legs Syndrome may not be the most appropriate term to denote this \nnosological entity.",
"BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as \nWillis-Ekbom disease (WED), varies from country to country, and methodologic \ninconsistencies limit comparison of data. Impact of RLS on quality of life and \nhealth has been studied primarily in industrialized countries, particularly \nEurope and the United States. Many studies have relied exclusively on \nself-report of symptoms or have assessed only medical populations. Recently, \ninterest has emerged on the impact of WED in rural, underserved populations \nglobally.\nMETHODS: In a population-based survey conducted in rural Ecuador, we assessed \nthe relationship of psychological distress to WED, evaluated with the Depression \nAnxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which \nall residents were screened with the International Restless Legs Syndrome Study \nGroup (IRLSSG) questionnaire and all suspected cases were subsequently confirmed \nthrough expert medical examination. WED severity was assessed with the IRLSSG \nrating scale.\nRESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 \nhad depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had \nWED, with 15 (38%) having severe disease. In a regression model adjusted for age \nand sex, the prevalence of depression, anxiety, and stress was about 3 times \ngreater among persons with WED than the general population.\nCONCLUSIONS: Although cross-sectional data cannot establish causation, this \nstudy shows the large behavioral health burden associated with WED in an \nuntreated, rural population.",
"Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a \ncommon movement disorder characterised by an uncontrollable urge to move because \nof uncomfortable, sometimes painful sensations in the legs with a diurnal \nvariation and a release with movement. The pathophysiology is only partially \nknown and a genetic component together with dopaminergic and brain iron \ndysregulation plays an important role. Secondary causes for RLS need to be \nexcluded. Treatment depends on the severity and frequency of RLS symptoms, \ncomprises non-pharmacological (eg lifestyle changes) and pharmacological \ninterventions (eg dopaminergic medication, alpha-2-delta calcium channel \nligands, opioids) and relieves symptoms only. Augmentation is the main \ncomplication of long-term dopaminergic treatment of RLS. This article will \nprovide a clinically useful overview of RLS with provision of diagnostic \ncriteria, differential diagnoses, possible investigations and different \ntreatment strategies with their associated complications.",
"Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a \nsensory-motor neurological disorder with a circadian component. RLS is \ncharacterized by uncomfortable sensations in the extremities, generally at night \nor during sleep, which often leads to an uncontrollable urge to move them for \nrelief. Recently, genomic studies identified single-nucleotide polymorphisms in \nBTBD9, along with three other genes, as being associated with a higher risk of \nRLS. Little is known about the function of BTBD9 or its potential role in the \npathophysiology of RLS. We therefore examined a line of Btbd9 mutant mice we \nrecently generated for phenotypes similar to symptoms found in RLS patients. We \nobserved that the Btbd9 mutant mice had motor restlessness, sensory alterations \nlikely limited to the rest phase, and decreased sleep and increased wake times \nduring the rest phase. Additionally, the Btbd9 mutant mice had altered serum \niron levels and monoamine neurotransmitter systems. Furthermore, the sensory \nalterations in the Btbd9 mutant mice were relieved using ropinirole, a \ndopaminergic agonist widely used for RLS treatment. These results, taken \ntogether, suggest that the Btbd9 mutant mice model several characteristics \nsimilar to RLS and would therefore be the first genotypic mouse model of RLS. \nFurthermore, our data provide further evidence that BTBD9 is involved in RLS, \nand future studies of the Btbd9 mutant mice will help shine light on its role in \nthe pathophysiology of RLS. Finally, our data argue for the utility of Btbd9 \nmutant mice to discover and screen novel therapeutics for RLS.",
"A Task Force was established by the International Restless Legs Syndrome Study \nGroup (IRLSSG) to develop evidence-based and consensus-based recommendations for \nthe long-term pharmacologic treatment of restless legs syndrome/Willis-Ekbom \ndisease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED \ntreatments with durations of 6 months or longer presented at meetings over the \npast 2 years, posted on Web sites of pharmaceutical companies, or published in \npeer-reviewed journals, asking the questions, \"What is the efficacy of this \ntreatment in patients with RLS/WED?\" and \"What is the safety of this treatment \nin patients with RLS/WED?\" The Task Force developed guidelines based on their \nreview of 61 papers meeting inclusion criteria, and using a modified \nevidence-grading scheme. Pregabalin has been established as effective for up to \n1 year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and \nrotigotine have been established as effective for up to 6 months in treating \nRLS/WED (Level A). The following drugs have been established as probably \neffective (Level B) in treating RLS/WED for durations ranging from 1 to 5 years: \ngabapentin enacarbil, pramipexole, and ropinirole (1 year); levodopa (2 years); \nand rotigotine (5 years). Because of associated safety concerns, pergolide and \ncabergoline should not be used in the treatment of RLS/WED unless the benefits \nclearly outweigh the risks. Other pharmacologic therapies have insufficient \nevidence to support their long-term use in treating RLS/WED. The IRLSSG Task \nForce also developed consensus-based strategies for the prevention and treatment \nof complications (such as augmentation, loss of efficacy, excessive daytime \nsleepiness, and impulse control disorders) that may develop with the long-term \npharmacologic treatment of RLS/WED. The use of either a dopamine-receptor \nagonist or α2δ calcium-channel ligand is recommended as the first-line treatment \nof RLS/WED for most patients, with the choice of agent dependent on the \npatient's severity of RLS/WED symptoms, cognitive status, history, and comorbid \nconditions.",
"OBJECTIVE: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is \na sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED \non motor function. The current study investigated upper limb function in RLS/WED \npatients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor \namplitude but normal dexterity and movement speed and rhythmicity compared to \nhealthy controls.\nMETHODS: RLS/WED patients (n=17, 59 ± 7 years) with moderate disease and healthy \ncontrols (n=17, 58 ± 6 years) completed screening tests and five tasks including \nobject manipulation, maximal pinch grip, flexion and extension of the index \nfinger (tremor assessment), maximal finger tapping (movement speed and \nrhythmicity assessment), and the grooved pegboard test. Force, acceleration, \nand/or first dorsal interosseus EMG were recorded during four of the tasks.\nRESULTS: Task performance did not differ between groups. Learning was evident on \ntasks with repeated trials and the magnitude of learning did not differ between \ngroups.\nCONCLUSIONS: Hand function, tremor, and task learning were unaffected in RLS/WED \npatients. Patients manipulated objects in a normal manner and exhibited normal \nmovement speed, rhythmicity, and tremor.\nSIGNIFICANCE: Further research is needed to assess other types of movement in \nRLS/WED patients to gain insight into the motor circuitry affected and the \nunderlying pathophysiology.",
"There is no consensus about mechanisms underlying restless legs syndrome (RLS), \nalso known as Willis-Ekbom disease (WED). Cortical excitability may be abnormal \nin RLS. Transcranial magnetic stimulation (TMS) can provide insight about \ncortical excitability. We reviewed studies about measures of excitability to TMS \nin RLS. Original studies published between January 1999 and January 2015 were \nsearched in PubMed, Scopus, and Web of Science databases. Inclusion criteria \nwere as follows: original studies involving primary RLS in patients from both \nsexes and ages between 18 and 85 years; TMS protocols clearly described; and \nthey were written in English, in peer-reviewed journals. Fifteen manuscripts \nwere identified. TMS protocols were heterogeneous across studies. Resting motor \nthreshold, active motor threshold, and amplitudes of motor-evoked potentials \nwere typically reported to be normal in RLS. A reduction in short-interval \nintracortical inhibition (SICI) was the most consistent finding, whereas \nconflicting results were described in regard to short-interval intracortical \nfacilitation and the contralateral silent period. Decreased SICI can be reversed \nby treatment with dopaminergic agonists. Plasticity in the motor cortex and \nsensorimotor integration may be disrupted. TMS may become a useful biomarker of \nresponsiveness to drug treatment in RLS. The field can benefit from increases in \nhomogeneity and sizes of samples, as well as from decrease in methodological \nvariability across studies.",
"OBJECTIVES: Both restless legs syndrome ([RLS], also known as Willis-Ekbom \nDisease [WED]) and depression are common during pregnancy. However, no prior \nstudies have assessed if pregnant women with RLS have an elevated risk of \ndepression during and/or after pregnancy.\nMETHODS: 1,428 women who were pregnant in gestational week 16-17 were asked to \nparticipate in a longitudinal survey. They were followed by web-based \nquestionnaires in gestational week 17 and 32, and 6 weeks after delivery. Data \nwere also retrieved from prenatal and birth records. Two different sets of \ncriteria were used to examine the prevalence of RLS in the cohort (International \nRestless Legs Syndrome Society Group standard criteria and the later developed \nCH-RLSQ11 questionnaire). The latter questionnaire attempts to exclude those \nwith common \"mimics\" of RLS.\nRESULTS: Adjusted odds ratio for depression in gestational week 17, 32, and \npostpartum week 6 in relation to pre-pregnancy RLS onset and moderate to severe \nsymptom severity were 4.74 (2.30 - 9.76), 3.67 (1.85 - 7.28), and 2.58 (1.28 - \n5.21), respectively. No significant associations were seen in pregnant women \nwith de novo RLS during pregnancy. When using the standard diagnostic RLS \ncriteria and frequency of symptoms more than 2-3 days per week, the prevalence \nof RLS was 12.3%. With the CH-RLSQ11 questionnaire and the same threshold for \nfrequency of symptoms the prevalence was 6.5%.\nCONCLUSION: Women with RLS onset before pregnancy with moderate or severe \nsymptoms had an increased risk of both antenatal and postnatal depression. The \nself-reported prevalence of RLS during pregnancy is lower when a questionnaire \ndealing with \"mimics\" is used.",
"BACKGROUND: Willis-Ekbom disease (WED), also called restless legs syndrome \n(RLS), is a neurologic sensorimotor disease that may be associated with \ncardiovascular disease. Given high morbidity and mortality rates of \ncardiovascular disease worldwide, we assessed the relation between WED/RLS and \ncardiovascular health risks in a native South American population. We \nprospectively analyzed data from The Atahualpa Project of Ecuadorian adults aged \n40 years and older. Physicians interviewed consented persons on the health \nbehavior and health factors of the American Heart Association (AHA) for ideal \ncardiovascular health in adults and underwent fasting laboratory blood \ncollection and blood pressure evaluation. Certified neurologists conducted \nface-to-face interviews using the International Restless Legs Syndrome Study \nGroup (IRLSSG) field instrument. Persons testing positive for WED/RLS and \nage-and sex-matched controls underwent confirmatory physical examinations \nconducted by a neurologist and a sleep specialist to whom IRLSSG designation was \nblinded.\nFINDINGS: Of 665 persons, 94 (14 %) tested positive in IRLSSG; 40 (6 %) had a \ndiagnosis of WED/RLS after neurologic examination and interview. Patients with \nWED/RLS were younger (53.5 vs 59.9 years, P = .001), without significant \ndifferences in sex ratios. Among AHA risk factors, only obesity was \nsignificantly more prevalent among patients with WED/RLS (42.5 % vs 23.5 %, \nP = .01). However, after adjustment for confounders, body mass index was not \nsignificantly associated with WED/RLS.\nCONCLUSIONS: In adult Amerindians, although obesity and body mass index were \nassociated with WED/RLS on univariate analyses, the association was not present \nafter adjustment for confounders. No other significant associations were found \nbetween WED/RLS and AHA cardiovascular metrics.",
"Untreated sleep disorders may contribute to secondary causes of uncontrolled \nhypertension, cardiovascular disease (CVD), and stroke. Restless legs syndrome, \nor Willis-Ekbom Disease (RLS/WED), is a common sensorimotor disorder with a \ncircadian rhythmicity defined by an uncontrollable urge to move the legs that \nworsens during periods of inactivity or at rest in the evening, often resulting \nin sleep disruptions. Sleep disorders such as insomnia and obstructive sleep \napnea (OSA) are established risk factors for increased risk of hypertension and \nvascular diseases. This literature review outlines the lessons learned from \nstudies demonstrating insomnia and OSA as risk factors for hypertension and \nvascular diseases to support the epidemiologic and physiologic evidence \nsuggesting a similar increase in hypertension and vascular disease risk due to \nRLS. Understanding the relationships between RLS and hypertension, CVD, and \nstroke has important implications for reducing the risks associated with these \ndiseases.",
"Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is a common disorder, \noccurring at least twice a week and causing at least moderate distress in 1.5% \nto 2.7% of the population. It is important for primary care physicians to be \nfamiliar with this disorder and its management. Much has changed in its \nmanagement since our previous algorithm was published in 2004, including the \navailability of several new drugs. This revised algorithm was written by members \nof the Medical Advisory Board of the Willis-Ekbom Disease Syndrome Foundation \nbased on scientific evidence and expert opinion. It considers the management of \nRLS/WED under intermittent RLS/WED, chronic persistent RLS/WED, and refractory \nRLS/WED. Nonpharmacological approaches, including mental alerting activities, \navoiding substances or medications that may exacerbate RLS, and the role of iron \nsupplementation, are outlined. Chronic persistent RLS/WED should be treated with \neither a nonergot dopamine agonist or a calcium channel α-2-δ ligand. We discuss \nthe available drugs, the factors determining which to use, and their adverse \neffects. We define refractory RLS/WED and describe management approaches, \nincluding combination therapy and the use of high-potency opioids.",
"Restless leg syndrome/Willis-Ekbom disease has brain iron deficiency that \nproduces excessive dopamine and known genetic risks, some of which contribute to \nthe brain iron deficiency. Dopamine treatments work temporarily but may \neventually produce further postsynaptic down-regulation and worse restless leg \nsyndrome. This article includes sections focused on pathophysiologic findings \nfrom each of these areas: genetics, cortical-spinal excitability, and iron and \ndopamine.",
"Sleep disorders are frequent comorbidities in neurologic patients. This review \nfocuses on clinical aspects and prognosis of 3 neurologic sleep disorders: \nnarcolepsy, restless legs syndrome/Willis-Ekbom disease (RLS/WED), and REM sleep \nbehavior disorder (RBD). Narcolepsy causes pervasive, enduring excessive daytime \nsleepiness, adversely affecting patients' daily functioning. RLS/WED is \ncharacterized by an uncomfortable urge to move the legs before sleep, often \nevolving toward augmentation and resulting in daylong bothersome symptoms. RBD \ncauses potentially injurious dream enactment behaviors that often signify future \nevolution of overt synucleinopathy neurodegeneration in as many as 81% of \npatients. Timely recognition, referral for polysomnography, and longitudinal \nfollow-up of narcolepsy, RLS/WED, and RBD patients are imperatives for \nneurologists in providing quality comprehensive patient care.",
"Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a common condition \ncharacterized by an irresistible urge to move the legs, concomitant with an \nunpleasant sensation in the lower limbs, which is typically relieved by \nmovement. Symptoms occur predominantly at rest and prevail in the afternoon or \nevening. Treatment of patients with RLS/WED is indicated for those patients who \nsuffer from clinically relevant symptoms. The management of mild forms of \nRLS/WED is mainly based on dopamine agonists (DA) therapy (including pramipexole \nand ropinirole) and α-2-δ calcium-channel ligand. Nevertheless, with passing of \ntime, symptoms tend to become more severe and the patient can eventually develop \npharmacoresistance. Furthermore, long-term treatment with dopaminergic agents \nmay be complicated by the development of augmentation, which is defined by an \nincrease in the severity and frequency of RLS/WED symptoms despite adequate \ntreatment. Here, we discuss which are the best therapeutic options when RLS/WED \nbecomes intractable, with a focus on advantages and side effects of the \navailable medications. Prevention strategies include managing lifestyle changes \nand a good sleep hygiene. Different drug options are available. Switching to \nlonger-acting dopaminergic agents may be a possibility if the patient is \nwell-tolerating DA treatment. An association with α-2-δ calcium-channel ligand \nis another first-line approach. In refractory RLS/WED, opioids such as \noxycodone-naloxone have demonstrated good efficacy. Other pharmacological \napproaches include IV iron, benzodiazepines such as clonazepam, and \nantiepileptic drugs, with different level of evidence of efficacy. Therefore, \nthe final decision regarding the agent to use in treating severe RLS/WED \nsymptoms should be tailored to the patient, taking into account the \nsymptomatology, comorbidities, the availability of treatment and the history of \nthe disease.",
"Many patients with restless legs syndrome (Willis-Ekbom disease) complain of \nburning sensations in their feet associated with the desire to move, such that \nthey seek cooler environments. This pilot study aimed to characterise the \nmicrovascular skin changes in 12 patients with restless legs syndrome compared \nwith 12 age- and sex-matched controls. Patients with moderate or severe restless \nlegs syndrome and controls underwent detailed thermovascular assessment in a \ncontrolled temperature room at three different stages (normothermic phase 23 °C, \nhot phase 30 °C, cold phase 18 °C). Microvascular activity was recorded during \nall phases by bilateral great toe laser-Doppler flowmetry and also by whole-body \nthermography. Patient and control measurements were compared. The study protocol \nwas well tolerated. Parameters extracted from the laser-Doppler flowmetry \nmeasurements were used to model a logistic function using binary logistic \nregression. This demonstrated a statistically significant difference between \npatients with restless legs syndrome and healthy controls (P < 0.001). Visual \ninspection of the body thermography image sequences showed increased lower limb \nmovement in patients with restless legs syndrome patients compared with \ncontrols. Thermography analysis also showed significant differences between foot \ntemperatures in patients with restless legs syndrome compared with controls \nduring the hot phase (P = 0.011). Notably, patients with restless legs syndrome \nhad more uniform foot temperatures, whereas controls had a wider variability in \nsurface temperature across the feet. This novel study demonstrates impaired \nmicrovascular circulation in patients with restless legs syndrome in comparison \nto matched controls and a potential mechanism for the sensation of burning feet. \nThe protocol also provides an experimental paradigm to test therapeutic \ninterventions for the future.",
"Clinical features variability between familial and sporadic restless legs \nsyndrome/Willis-Ekbom disease (RLS/WED) has been previously reported. With this \nretrospective cohort study, we aimed to determine the clinical and \npolysomnographic characteristics of 400 RLS/WED patients. Patients with familial \nRLS/WED were significantly younger than sporadic RLS/WED, while clinical and \npolysomnographic characteristics were similar in both groups. No difference was \nfound for the age-at-onset between idiopathic and secondary RLS/WED. Periodic \nlimb movements (PLM) index and REM sleep time were higher in idiopathic RLS/WED. \nTime of onset of symptoms was in the evening or at bedtime in 28.04 and 37.80% \nof patients, respectively, while in 21.34% of patients onset was more than 1 h \nafter sleep onset. Impulse control and compulsive behaviours (ICBs) were found \nin 13.29% patients on dopamine agonist therapy. Our analyses support the \nhypothesis that patients with a familial history of RLS/WED may have a genetic \ncomponent. Nevertheless, the dichotomy between early and late onset disease \nseems to be less sharp than previously reported. A large proportion of RLS/WED \npatients can have atypical features, therefore making the diagnosis challenging. \nSome cases can be missed even when the patient refers to a sleep specialist, as \nrevealed by the partial absence of daytime symptoms, the high comorbidity with \ninsomnia and other sleep complaints and the high percentage of symptoms \nbeginning after sleep onset. This draws attention on the importance of a careful \nevaluation of the patient, to recognize potentially treatable secondary forms of \nRLS/WED.",
"The article briefly summarizes the milestones leading to current knowledge and \nthe possibility of treating one of the most widespread and perhaps least known \ndiseases, restless legs syndrome (RLS). Until the mid-twentieth century, the \nsyndrome first described by Willis (1685), was sporadically reported in medical \nliterature and in most cases deemed a bizzare condition. It was only with \nEkbom's detailed clinical description of the syndrome (1944) and the polygraphic \nrecordings of Coccagna et al. (1962) that RLS became well-recognised clinical \nentity. Since then, almost all sleep laboratories have devoted much of their \nresearch to discovering the pathogenetic mechanisms underlying the disease and \ndevise increasingly specific treatment. Major advances have been made in recent \nyears, but a full understanding of RLS is still a long way off.",
"Restless legs syndrome/Willis Ekbom disease (RLS/WED) has been recognized as a \nsignificant medical disorder since the 17th century. It was studied mostly in \nthe last 50 years in relation to increasing interest in sleep medicine and \nhealth-related quality of life. This led to recognition that the disease is not \nwell characterized as restless feelings in the legs. These symptoms are reported \nin many situations, but the subjective experience of RLS/WED patients differs \nfrom that experienced by others. Thus a new name has been introduced that avoids \nproblems of symptom definition of a disease by naming it after those who first \ncharacterized it, i.e. 'Willis Ekbom disease'. This article emphasizes the \nimportance of RLS/WED for psychiatry. The disease carries significant increased \nrisk for depression and anxiety disorders. Treatment requires consideration of \nthese co-morbid disorders. RLS/WED can exacerbate or even engender psychiatric \ndisease, so treatment of psychiatric disease should also include consideration \nof RLS/WED. The need for attention to RLS/WED is particularly significant for \ndepression. Most anti-depressants exacerbate or can even engender RLS/WED. Thus \nthis article seeks to introduce RLS/WED in relation to psychiatric practice. It \npresents the RLS/WED disease, its overlap with psychiatry and the current \ntreatment options.",
"Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is commonly seen in \npatients with end-stage renal disease (ESRD), but this condition has not been \nproperly recognized. The prevalence of RLS/WED in ESRD shows the ethnic \nvariation (7%-68%), with the similar tendency of primary RLS/WED. Although \nRLS/WED in ESRD is defined in secondary RLS/WED, the factors of ESRD that are \ninvolved in the genesis of RLS/WED remain unknown. Even after renal \ntransplantation, RLS/WED symptoms do not completely disappear, and genetic \npredisposition to RLS/WED may play an important role in causing RLS/WED. \nLong-term intervention for RLS/WED and ESRD will be necessary.",
"Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) has a significant \nnegative effect on quality of life. The decreased quality of life is similar to \nthat of other chronic diseases, such as diabetes type 2, depression, and \nosteoarthritis. RLS/WED disrupts sleep length, sleep quality, and daytime \nalertness. Sleep disruption can contribute to depression. RLS/WED has been \nassociated with cardiovascular disease and high blood pressure, possibly because \nof increased sympathetic tone caused by periodic limb movements of sleep. \nRLS/WED is underdiagnosed, leading to chronic sleep disruption and daytime \nconsequences. Patients with RLS/WED have decreased productivity at work, which \npotentially has far-reaching economic consequences.",
"BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of \nrotigotine over placebo in improving symptom severity of restless legs syndrome \n(RLS), also known as Willis-Ekbom disease, on the International Restless Legs \nSyndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 \n(CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life \nquestionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To \nprovide clinical context for the IRLS and to guide the choice of assessment \nscales for RLS studies, our post hoc analysis of SP790 data evaluated \nassociations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and \nRLS-QoL.\nMETHODS: Scale associations were analyzed at baseline and at the end of \nmaintenance (EoM) using data from the safety set (rotigotine and placebo groups \ncombined [n=458]). Changes from baseline to EoM in IRLS score vs comparator \nscale scores also were analyzed.\nRESULTS: There was a trend towards increasing IRLS severity category with \nincreasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation \ncoefficients showed correlations between IRLS and comparator scale scores at \nbaseline and EoM as well as correlations for change from baseline to EoM.\nCONCLUSION: Correlations between the IRLS and comparator scales were \nsubstantial. These data indicate that the IRLS is clinically meaningful. The \nIRLS and CGI-1 are generally sufficient to evaluate the overall severity and \nimpact of RLS symptoms in clinical trials.",
"Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a \nsensorimotor disorder for which the exact pathophysiology remains unclear. Brain \niron insufficiency and altered dopaminergic function appear to play important \nroles in the etiology of the disorder. This concept is based partly on extensive \nresearch studies using cerebrospinal fluid (CSF), autopsy material, and brain \nimaging indicating reduced regional brain iron and on the clinical efficacy of \ndopamine receptor agonists for alleviating RLS symptoms. Finding causal \nrelations, linking low brain iron to altered dopaminergic function in RLS, has \nrequired however the use of animal models. These models have provided insights \ninto how alterations in brain iron homeostasis and dopaminergic system may be \ninvolved in RLS. The results of animal models of RLS and biochemical, \npostmortem, and imaging studies in patients with the disease suggest that \ndisruptions in brain iron trafficking lead to disturbances in striatal dopamine \nneurotransmission for at least some patients with RLS. This review examines the \ndata supporting an iron deficiency-dopamine metabolic theory of RLS by relating \nthe results from animal model investigations of the influence of brain iron \ndeficiency on dopaminergic systems to data from clinical studies in patients \nwith RLS.",
"OBJECTIVE: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is \na sensorimotor disorder that can result in considerable sleep disruption. This \nnarrative review provides an overview of RLS diagnosis and reports epidemiologic \nevidence for an association between RLS and mood disorders. Possible links \nbetween RLS, sleep disturbances, and mood disorders are considered, and \ntheoretical pathophysiologic pathways are discussed. Finally, pharmacologic \ntherapies for RLS are summarized.\nDATA SOURCES: A PubMed search was performed using the search term restless legs \nsyndrome in combination with affective/anxiety, antidepressants, anxiety/anxiety \ndisorder, attention deficit hyperactivity disorder, depression/depressive \ndisorder, mood/mood disorder, neuropsychiatric, panic/panic disorder, \npsychiatric disorder, and psychosis. English-language articles published between \nJanuary 1993 and May 2013 were retrieved. Additional studies were identified \nfrom the reference lists of relevant publications.\nSTUDY SELECTION: 173 publications were retrieved. Articles related to the \nassociation between idiopathic RLS and depression, anxiety, and mood disorders \nwere reviewed. In total, 32 epidemiologic studies were identified. These studies \nwere reviewed in detail and ranked according to quality.\nDATA EXTRACTION: Data were extracted on the basis of relevance to the topic. \nEpidemiologic studies were assessed using 3 parameters: methodology, data \nquality, and generalizability of the results. Each factor was scored from 1 \n(high quality) to 4 (low quality), giving a total score of between 3 and 12 for \neach study.\nRESULTS AND CONCLUSIONS: RLS and mood disorders are frequently comorbid. \nRecognition and appropriate treatment of comorbid RLS are particularly important \nin patients with psychiatric disorders, as RLS is a common medical reason for \ninsomnia, and antidepressant use may exacerbate sensory symptoms.",
"STUDY OBJECTIVES: Recent genome-wide association studies (GWAS) for Caucasians \nidentified several allelic variants associated with increased risk of developing \nrestless legs syndrome (RLS), also known as Willis-Ekbom disease. Although the \npathogenic mechanisms of RLS are not entirely understood, it is becoming \nincreasingly evident that many diseases such as RLS can be attributed to an \nepistasis. The study objectives were to evaluate whether the associations of RLS \nwith all loci determined in previous GWAS for Caucasians can be replicated \nsignificantly for the Korean population and to elucidate whether an epistasis \nplays a role in the pathogenesis of RLS.\nDESIGN SETTING AND PARTICIPANTS: DNA from 320 patients with RLS and 320 age- and \nsex-matched controls were genotyped for variants in the RLS loci.\nMEASUREMENTS AND RESULTS: A significant association was found for rs3923809 and \nrs9296249 in BTBD9 (P < 0.0001 and P = 0.001, respectively); the odds ratio (OR) \nfor rs3923809 was 1.61 (P < 0.0001) to 1.88 (P < 0.0001) and the OR for \nrs9296249 was 1.44 (P = 0.001) to 1.73 (P = 0.002), according to the model of \ninheritance. The OR for the interaction between rs3923809 in BTBD9 and rs4626664 \nin PTPRD was 2.05 (P < 0.0001) in the additive model, 1.80 (P = 0.002) in the \ndominant model and 2.47 (P = 0.004) in the recessive model. There was no \nsignificant association between genotypes of all tested single nucleotide \npolymorphisms and the mean value of serum iron parameters.\nCONCLUSIONS: Our results suggest that the role of BTBD9 in the pathogenesis of \nrestless legs syndrome is more universal across populations than previously \nreported and more efforts should be focused on the role of epistasis in the \ngenetic architecture of restless legs syndrome.",
"INTRODUCTION: Restless legs syndrome (RLS), also known as Willis-Ekbom disease, \nis characterised by abnormal sensations in the legs as well as dysaesthesia. \nAlthough the aetiology of RLS has not yet been determined, it may be associated \nwith systemic inflammation. The neutrophil-to-lymphocyte ratio (NLR) is a new \nand simple marker indicating systemic inflammation. The present study aimed to \ninvestigate the relationship between systemic inflammation and RLS through the \nuse of the NLR.\nMETHODS: A total of 75 newly diagnosed patients with RLS and 56 healthy control \nsubjects were included in the study. Baseline NLR was calculated by dividing the \nabsolute neutrophil count by the absolute lymphocyte count. The NLRs of the two \ngroups were compared.\nRESULTS: There were no significant differences in gender and age between the two \ngroups. The NLR was 1.96 ± 0.66 in the patient group and 1.67 ± 0.68 in the \ncontrol group (p = 0.005). Receiver operating characteristic analysis was \nperformed to determine the cut-off value of NLR to predict RLS. The NLR was \npredictive at 1.58 with a 64% sensitivity and 50% specificity (95% confidence \ninterval 0.55-0.74, area under curve 0.648 ± 0.05). The NLR was found to be \nstatistically higher in patients with RLS and may be used to predict RLS.\nCONCLUSION: The aetiology of RLS remains undetermined. The present study showed \nthat systemic inflammation may play a role in RLS. However, RLS could also be \nassociated with systemic inflammatory diseases. This relationship is supported \nby high NLR values, which are related to chronic systemic inflammation."
] | nan |
5a86f074faa1ab7d2e00003a | [
28427232,
28825187,
27635948,
24983247,
28812319
] | train | With which cancers has the loss of SMARCB1 been associated? | factoid | Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1 Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs) | chordomas or childhood chordomas or infantile chordomas or CCs | [
"Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of \ninfancy, characterized by undifferentiated histological features and loss of \nSMARCB1 expression. The diagnosis is all the more challenging that other poorly \ndifferentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas \n(ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). \nMoreover, late cases occurring in adults are now increasingly reported, raising \nthe question of differential diagnoses and emphasizing nosological issues. To \naddress this issue, we have analyzed the expression profiles of a training set \nof 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, \nall < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n \n= 5). As compared with other SDT, RT are characterized by an embryonic \nsignature, and up-regulation of key-actors of de novo DNA methylation processes. \nUsing this signature, we then analysed the expression profiling of 37 SDT to \ninfer the appropriate diagnosis. Thirteen adult onset tumors showed strong \nsimilarity with pediatric RT, in spite of older age; by exome sequencing, these \ntumors also showed genomic features indistinguishable from pediatric RT. In \ncontrary, 8 tumors were reclassified within carcinoma, ES or UC categories, \nwhile the remaining could not be related to any of those entities. Our results \ndemonstrate that embryonic signature is shared by all RT, whatever the age at \ndiagnosis; they also illustrate that many adult-onset SDT of ambiguous \nhistological diagnosis are clearly different from RT. Finally, our study paves \nthe way for the routine use of expression-based signatures to give accurate \ndiagnosis of SDT.",
"Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood \nchordomas (CCs). Although mutation/loss of 22q has strongly established the loss \nof SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies \nsuggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 \nreported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative \nand immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p \nin SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were \nsignificantly predicted to target TGF-β signaling, suggestive of dysregulation \nof developmental and osteoblast regulation pathway in CCs. Overall, we suggest \nmiR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and \ndownregulated TGF-β pathway in CCs.",
"Chordomas arise in the skull base and spine and usually occur in adults and are \nrare in the pediatric population. Cases of chordoma in pediatric age are often \npoorly differentiated, showing cytologic atypia, increased cellularity, and \nmitosis, and their aggressive behavior is associated with a high incidence of \nmetastatic spread and a short patient survival. Recent studies have described \nloss of SMARCB1/INI1 protein in poorly differentiated chordomas associated not \nwith point mutations but with SMARCB1/INI1 gene deletions instead. In this \nstudy, we considered immunohistochemistry and SMARCB1/INI1 mutational status to \nexamine SMARCB1 status in a series of pediatric chordomas (7 classic and 1 \npoorly differentiated). We performed immunohistochemical tests for INI1, \nbrachyury, S100, and cytokeratins and conducted a genetic analysis on the \nSMARCB1 coding sequence (NM_003073) using the Sanger method and multiplex \nligation-dependent probe amplification to detect abnormal copy numbers of the \ngene locus. All 8 cases were positive for brachyury, whereas there was no \nnuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly \ndifferentiated chordoma. Genetic analysis identified a missense mutation in 2 \ncases and a nonsense mutation associated with loss of SMARCB1/INI1 protein and \nfeatures of poorly differentiated tumor in 1. These mutations were novel \nvariants occurring in heterozygosity, and they were judged to be pathogenic by 3 \ndifferent bioinformatic tools. In 7 of 8 cases we performed multiplex \nligation-dependent probe amplification, and 3 cases showed deletions at the \nSMARCB1 locus. Our results confirm the pathogenic involvement of SMARCB1/INI1 in \nchildhood chordoma. We also describe 3 novel pathogenic mutations.",
"The molecular mechanisms underlying chordoma pathogenesis are unknown. We \ntherefore sought to identify novel mutations to better understand chordoma \nbiology and to potentially identify therapeutic targets. Given the relatively \nhigh costs of whole genome sequencing, we performed a focused genetic analysis \nusing matrix-assisted laser desorption/ionization-time of flight mass \nspectrometer (Sequenom iPLEX genotyping). We tested 865 hotspot mutations in 111 \noncogenes and selected tumor suppressor genes (OncoMap v. 3.0) of 45 human \nchordoma tumor samples. Of the analyzed samples, seven were identified with at \nleast one mutation. Six of these were from fresh frozen samples, and one was \nfrom a paraffin embedded sample. These observations were validated using an \nindependent platform using homogeneous mass extend MALDI-TOF (Sequenom hME \nGenotyping). These genetic alterations include: ALK (A877S), CTNNB1 (T41A), NRAS \n(Q61R), PIK3CA (E545K), PTEN (R130), CDKN2A (R58*), and SMARCB1 (R40*). This \nstudy reports on the largest comprehensive mutational analysis of chordomas \nperformed to date. To focus on mutations that have the greatest chance of \nclinical relevance, we tested only oncogenes and tumor suppressor genes that \nhave been previously implicated in the tumorigenesis of more common \nmalignancies. We identified rare genetic changes that may have functional \nsignificance to the underlying biology and potential therapeutics for chordomas. \nMutations in CDKN2A and PTEN occurred in areas of chromosomal copy loss. When \nthis data is paired with the studies showing 18 of 21 chordoma samples \ndisplaying copy loss at the locus for CDKN2A, 17 of 21 chordoma samples \ndisplaying copy loss at PTEN, and 3 of 4 chordoma samples displaying deletion at \nthe SMARCB1 locus, we can infer that a loss of heterozygosity at these three \nloci may play a significant role in chordoma pathogenesis.",
"Identification of loss of SMARCB1/INI1 expression in poorly differentiated (PD) \nchordoma in pediatric patients suggests that PD chordoma is an entity \nmolecularly distinct from conventional chordoma or atypical teratoid/rhabdoid \ntumor, which is also characterized by loss of SMARCB1/INI1 expression by \ninactivating mutation of the SMARCB1/INI gene. So far, around 20 cases of \npediatric PD chordoma with loss of SMARCB1/INI1 expression have been reported. \nHere, we report two cases of pediatric PD chordoma with loss of SMARCB1/INI1 \nexpression, which is very rare among the pediatric chordoma types. Both patients \npresented clival masses on preoperative MRI. Histologically, both tumors had \nnonclassic histologic features for conventional chordoma: sheets of large \nepithelioid to spindle cells with vesicular nuclei and prominent nucleoli. Both \ncases revealed nuclear expression of brachyury, loss of SMARCB1/INI1 expression \nand lack of embryonal, neuroectodermal, or epithelial component. One case showed \nheterozygous loss of EWSR1 gene by break-apart fluorescence in situ \nhybridization that reflected loss of SMARCB1/INI1 gene. Based on the clival \nlocation and histologic findings along with the loss of SMARCB1/INI1 expression \nand positivity for nuclear brachyury staining, the final pathologic diagnosis \nfor both cases was PD chordoma."
] | nan |
56b773a96e3f8eaf4c000003 | [
22771212,
20395473,
24705649,
22499857,
20230609,
24509845,
25526805,
20007317,
23599000,
21749979,
20434206
] | train | With which complexes is the protein SUS1 associated? | list | Sus1/ENY2 is a component of the SAGA and TREX-2 complexes | ['SAGA complex', 'TREX-2 complex'] | [
"The deubiquitinating module (DUBm) of the SAGA coactivator contains the Ubp8 \nisopeptidase, Sgf11, Sus1, and Sgf73, which form a highly interconnected \ncomplex. Although Ubp8 contains a canonical USP catalytic domain, it is only \nactive when in complex with the other DUBm subunits. The Sgf11 zinc finger \n(Sgf11-ZnF) binds near the Ubp8 active site and is essential for full activity, \nsuggesting that the Sgf11-ZnF helps maintain the active conformation of Ubp8. We \nreport structural and solution studies showing that deletion of the Sgf11-ZnF \ndestabilizes incorporation of Ubp8 within the DUBm, giving rise to domain \nswapping with a second complex and misaligning active site residues. Activating \nmutations in Ubp8 that partially restore activity in the absence of the \nSgf11-ZnF promote the monomeric form of the DUBm. Our data suggest an unexpected \nrole for Sgf11 in compensating for the absence of structural features that \nmaintain the active conformation of Ubp8.",
"SAGA is a transcriptional coactivator complex that is conserved across \neukaryotes and performs multiple functions during transcriptional activation and \nelongation. One role is deubiquitination of histone H2B, and this activity \nresides in a distinct subcomplex called the deubiquitinating module (DUBm), \nwhich contains the ubiquitin-specific protease Ubp8, bound to Sgf11, Sus1, and \nSgf73. The deubiquitinating activity depends on the presence of all four DUBm \nproteins. We report here the 1.90 angstrom resolution crystal structure of the \nDUBm bound to ubiquitin aldehyde, as well as the 2.45 angstrom resolution \nstructure of the uncomplexed DUBm. The structure reveals an arrangement of \nprotein domains that gives rise to a highly interconnected complex, which is \nstabilized by eight structural zinc atoms that are critical for enzymatic \nactivity. The structure suggests a model for how interactions with the other \nDUBm proteins activate Ubp8 and allows us to speculate about how the DUBm binds \nto monoubiquitinated histone H2B in nucleosomes.",
"The conserved Sac3:Thp1:Sem1:Sus1:Cdc31 (TREX2) complex binds to nuclear pore \ncomplexes (NPCs) and, in addition to integrating mRNA nuclear export with \npreceding steps in the gene expression pathway, facilitates re-positioning of \nhighly regulated actively transcribing genes (such as GAL1) to NPCs. Although \nTREX2 is thought to bind NPC protein Nup1, defining the precise role of this \ninteraction has been frustrated by the complex pleiotropic phenotype exhibited \nby nup1Δ strains. To provide a structural framework for understanding the \nbinding of TREX2 to NPCs and its function in the gene expression pathway, we \nhave determined the structure of the Nup1:TREX2 interaction interface and used \nthis information to engineer a Sac3 variant that impairs NPC binding while not \ncompromising TREX2 assembly. This variant inhibited the NPC association of both \nde-repressed and activated GAL1 and also produced mRNA export and growth \ndefects. These results indicate that the TREX2:Nup1 interaction facilitates the \nefficient nuclear export of bulk mRNA together with the re-positioning of GAL1 \nto NPCs that is required for transcriptional control that is mediated by removal \nof SUMO from repressors by NPC-bound Ulp1.",
"BACKGROUND AND AIMS: Differential responses of closely related species to \nsubmergence can provide insight into the evolution and mechanisms of submergence \ntolerance. Several traits of two wetland species from habitats with contrasting \nflooding regimes, Rorippa amphibia and Rorippa sylvestris, as well as F(1) \nhybrid Rorippa × anceps were analysed to unravel mechanisms underlying \nsubmergence tolerance.\nMETHODS: In the first submergence experiment (lasting 20 d) we analysed biomass, \nstem elongation and carbohydrate content. In the second submergence experiment \n(lasting 3 months) we analysed survival and the effect of re-establishment of \nair contact on biomass and carbohydrate content. In a separate experiment we \nanalysed expression of two carbohydrate catabolism genes, ADH1 and SUS1, upon \nre-establishment of air contact following submergence.\nKEY RESULTS: All plants had low mortality even after 3 months of submergence. \nRorippa sylvestris was characterized by 100 % survival and higher carbohydrate \nlevels coupled with lower ADH1 gene expression as well as reduced growth \ncompared with R. amphibia. Rorippa amphibia and the hybrid elongated their stems \nbut this did not pay-off in higher survival when plants remained submerged. Only \nR. amphibia and the hybrid benefited in terms of increased biomass and \ncarbohydrate accumulation upon re-establishing air contact.\nCONCLUSIONS: Results demonstrate contrasting 'escape' and 'quiescence' \nstrategies between Rorippa species. Being a close relative of arabidopsis, \nRorippa is an excellent model for future studies on the molecular mechanism(s) \ncontrolling these strategies.",
"BACKGROUND: Gene expression is achieved by the coordinated action of multiple \nfactors to ensure a perfect synchrony from chromatin epigenetic regulation \nthrough to mRNA export. Sus1 is a conserved mRNA export/transcription factor and \nis a key player in coupling transcription initiation, elongation and mRNA \nexport. In the nucleus, Sus1 is associated to the transcriptional co-activator \nSAGA and to the NPC associated complex termed TREX2/THSC. Through these \nassociations, Sus1 mediates the nuclear dynamics of different gene loci and \nfacilitate the export of the new transcripts.\nRESULTS: In this study, we have investigated whether the yeast Sus1 protein is \nlinked to factors involved in mRNA degradation pathways. We provide evidence for \ngenetic interactions between SUS1 and genes coding for components of P-bodies \nsuch as PAT1, LSM1, LSM6 and DHH1. We demonstrate that SUS1 deletion is \nsynthetic lethal with 5'-->3' decay machinery components LSM1 and PAT1 and has a \nstrong genetic interaction with LSM6 and DHH1. Interestingly, Sus1 \noverexpression led to an accumulation of Sus1 in cytoplasmic granules, which can \nco-localise with components of P-bodies and stress granules. In addition, we \nhave identified novel physical interactions between Sus1 and factors associated \nto P-bodies/stress granules. Finally, absence of LSM1 and PAT1 slightly promotes \nthe Sus1-TREX2 association.\nCONCLUSIONS: In this study, we found genetic and biochemical association between \nSus1 and components responsible for cytoplasmic mRNA metabolism. Moreover, Sus1 \naccumulates in discrete cytoplasmic granules, which partially co-localise with \nP-bodies and stress granules under specific conditions. These interactions \nsuggest a role for Sus1 in gene expression during cytoplasmic mRNA metabolism in \naddition to its nuclear function.",
"The yeast Spt-Ada-Gcn5-acetyltransferase (SAGA) complex is a transcription \ncoactivator that contains a histone H2B deubiquitination activity mediated by \nits Ubp8 subunit. Full enzymatic activity requires the formation of a quaternary \ncomplex, the deubiquitination module (DUBm) of SAGA, which is composed of Ubp8, \nSus1, Sgf11, and Sgf73. The crystal structures of the DUBm have shed light on \nthe structure/function relationship of this complex. Specifically, both Sgf11 \nand Sgf73 contain zinc finger domains (ZnF) that appear essential for the DUBm \nactivity. Whereas Sgf73 N-terminal ZnF is important for DUBm stability, Sgf11 \nC-terminal ZnF appears to be involved in DUBm function. To further characterize \nthe role of these two zinc fingers, we have solved their structure by NMR. We \nshow that, contrary to the previously reported structures, Sgf73 ZnF adopts a \nC2H2 coordination with unusual tautomeric forms for the coordinating histidines. \nWe further report that the Sgf11 ZnF, but not the Sgf73 ZnF, binds to \nnucleosomal DNA with a binding interface composed of arginine residues located \nwithin the ZnF α-helix. Mutational analyses both in vitro and in vivo provide \nevidence for the functional relevance of our structural observations. The \ncombined interpretation of our results leads to an uncommon ZnF-DNA interaction \nbetween the SAGA DUBm and nucleosomes, thus providing further functional \ninsights into SAGA's epigenetic modulation of the chromatin structure.",
"The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex performs multiple functions in \ntranscription activation including deubiquitinating histone H2B, which is \nmediated by a subcomplex called the deubiquitinating module (DUBm). The yeast \nDUBm comprises a catalytic subunit, Ubp8, and three additional subunits, Sgf11, \nSus1 and Sgf73, all of which are required for DUBm activity. A portion of the \nnon-globular Sgf73 subunit lies between the Ubp8 catalytic domain and the \nZnF-UBP domain and has been proposed to contribute to deubiquitinating activity \nby maintaining the catalytic domain in an active conformation. We report \nstructural and solution studies of the DUBm containing two different Sgf73 point \nmutations that disrupt deubiquitinating activity. We find that the Sgf73 \nmutations abrogate deubiquitinating activity by impacting the Ubp8 \nubiquitin-binding fingers region and they have an unexpected effect on the \noverall folding and stability of the DUBm complex. Taken together, our data \nsuggest a role for Sgf73 in maintaining both the organization and the \nubiquitin-binding conformation of Ubp8, thereby contributing to overall DUBm \nactivity.",
"Sus1 is a central component of the yeast gene gating machinery, the process by \nwhich actively transcribing genes such as GAL1 become associated with nuclear \npore complexes. Sus1 is a component of both the SAGA transcriptional \nco-activator complex and the TREX-2 complex that binds to nuclear pore \ncomplexes. TREX-2 contains two Sus1 chains that have an articulated helical \nhairpin fold, enabling them to wrap around an extended alpha-helix in Sac3, \nfollowing a helical hydrophobic stripe. In SAGA, Sus1 binds to Sgf11 and has \nbeen proposed to provide a link between SAGA and TREX-2. We present here the \ncrystal structure of the complex between Sus1 and the N-terminal region of Sgf11 \nthat forms an extended alpha-helix around which Sus1 wraps in a manner that \nshares some similarities with the Sus1-Sac3 interface in TREX-2. However, the \nSus1-binding site on Sgf11 is somewhat shorter than on Sac3 and is based on a \nnarrower hydrophobic stripe. Engineered mutants that disrupt the Sgf11-Sus1 \ninteraction in vitro confirm the importance of the hydrophobic helical stripe in \nmolecular recognition. Helix alpha1 of the Sus1-articulated hairpin does not \nbind directly to Sgf11 and adopts a wide range of conformations within and \nbetween crystal forms, consistent with the presence of a flexible hinge and also \nwith results from previous extensive mutagenesis studies (Klöckner, C., \nSchneider, M., Lutz, S., Jani, D., Kressler, D., Stewart, M., Hurt, E., and \nKöhler, A. (2009) J. Biol. Chem. 284, 12049-12056). A single Sus1 molecule \ncannot bind Sgf11 and Sac3 simultaneously and this, combined with the structure \nof the Sus1-Sgf11 complex, indicates that Sus1 forms separate subcomplexes \nwithin SAGA and TREX-2.",
"Transcription and mRNA export are linked processes. However, the molecular \nmechanisms of this coordination are not clear. Sus1 (hENY2) participates in this \ncoordination as part of two protein complexes: SAGA, a transcriptional \nco-activator; TREX-2, which functions in mRNA biogenesis and export. Here, we \ninvestigate the coordinated action of SAGA and TREX-2 required for gene \nexpression. We demonstrate that TREX-2 subunit Sem1 also participates in \ntranscription activation. Like Sus1, Sem1 is required for the induction of ARG1 \nand GAL1, these being SAGA-regulated genes. Chromatin immunoprecipitations show \nthat proper recruitment of certain SAGA subunits to the GAL1 promoter depends on \nSem1. Notably, both in vivo and in vitro analyses reveal that Sem1 influences \nSAGA-dependent histone H2B deubiquitylation. Most of these phenotypes are also \nfound to depend on another TREX-2 subunit, Thp1. These results unveil a new role \nfor Sem1 in the activation of the SAGA-dependent gene GAL1 and influencing H2B \ndeubiquitylation. Our work provides insights into a novel functional \nrelationship between Sem1 and the SAGA complex.",
"Efficient coupling between mRNA synthesis and export is essential for gene \nexpression. Sus1/ENY2, a component of the SAGA and TREX-2 complexes, is involved \nin both transcription and mRNA export. While most yeast genes lack introns, we \npreviously reported that yeast SUS1 bears two. Here we show that this feature is \nevolutionarily conserved and critical for Sus1 function. We determine that while \nSUS1 splicing is inefficient, it responds to cellular conditions, and intronic \nmutations either promoting or blocking splicing lead to defects in mRNA export \nand cell growth. Consistent with this, we find that an intron-less SUS1 only \npartially rescues sus1Δ phenotypes. Remarkably, splicing of each SUS1 intron is \nalso affected by the presence of the other and by SUS1 exonic sequences. \nMoreover, by following SUS1 RNA and protein levels we establish that \nnonsense-mediated decay (NMD) pathway and the splicing factor Mud2 both play a \nrole in SUS1 expression. Our data (and those of the accompanying work by Hossain \net al.) provide evidence of the involvement of splicing, translation, and decay \nin the regulation of early events in mRNP biogenesis; and imply the additional \nrequirement for a balance in splicing isoforms from a single gene.",
"Deubiquitinating enzymes (DUBs) regulate diverse cellular functions by cleaving \nubiquitin from specific protein substrates. How their activities are modulated \nin various cellular contexts remains poorly understood. The yeast deubiquitinase \nUbp8 protein is recruited and activated by the SAGA complex and, together with \nSgf11, Sus1, and Sgf73, forms a DUB module responsible for deubiquitinating \nhistone H2B during gene expression. Here, we report the crystal structure of the \ncomplete SAGA DUB module, which features two functional lobes structurally \ncoupled by Sgf73. In the \"assembly lobe,\" a long Sgf11 N-terminal helix is \nclamped onto the Ubp8 ZnF-UBP domain by Sus1. In the \"catalytic lobe,\" an Sgf11 \nC-terminal zinc-finger domain binds to the Ubp8 catalytic domain next to its \nactive site. Our structural and functional analyses reveal a central role of \nSgf11 and Sgf73 in activating Ubp8 for deubiquitinating histone H2B and \ndemonstrate how a DUB can be allosterically regulated by its nonsubstrate \npartners."
] | nan |
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